2-S-Benzyl Substituted Pyrimidines As CRTH2 Antagonists

ABSTRACT

Provided herein are 2-S-benzyl pyrimidine compounds having CRTH2 (G-protein-coupled chemoattractant receptor, expressed on Th2 cells) antagonistic activity, useful for the prophylaxis and treatment of diseases associated with CRTH2 activity, including the treatment of allergic diseases, eosinophil-related diseases and basophil-related diseases.

CLAIM OF PRIORITY

Priority is claimed herein to U.S. Provisional Patent Application No.60/995,387, entitled “2-S-benzyl substituted pyrimidines as CRTH2antagonists,” filed Sep. 25, 2007. The above-referenced application isincorporated by reference herein in its entirety.

FIELD OF THE INVENTION

Provided herein are 2-S-benzyl pyrimidine compounds having CRTH2(G-protein-coupled chemoattractant receptor, expressed on Th2 cells)antagonistic activity, useful for the prophylaxis and treatment ofdiseases associated with CRTH2 activity, including the treatment ofallergic diseases, eosinophil-related diseases and basophil-relateddiseases.

BACKGROUND

CRTH2 is a G protein-coupled chemoattractant receptor, expressed on Th2cells, eosinophils, and basophils (Nagata et al., J. Immunol.,162:1278-1286, 1999; Hirai et al., J. Exp. Med., 193: 255-261, 2001).

Th2 polarization has been observed in allergic diseases such as asthma,allergic rhinitis, atopic dermatitis and allergic conjunctivitis(Romagnani, S., Immunology Today, 18: 263-266, 1997; Hammad et al.,Blood, 98: 1135-1141, 2001). Th2 cells regulate allergic diseases byproducing Th2 cytokines such as IL-4, IL-5 and IL-13 (Oriss et al., J.Immunol., 162: 1999-2007, 1999; Viola et al., Blood, 91:2223-2230, 1998;Webb et al., J. Immunol., 165: 108-113, 2000; Dumont, F. J., Exp. Opin.Ther. Pat., 12: 341-367, 2002). These Th2 cytokines directly orindirectly induce migration, activiation, priming and prolonged survivalof effector cells, such as eosinophils and basophils, in allegicdiseases (Sanz et al., J. Immunol., 160: 5637-5645, 1998; Pope et al.,J. Allergy Clin. Immunol., 108: 594-601, 2001; Teran, L. M., Clin. Exp.Allergy, 29: 287-290, 1999).

Prostaglandin D₂ (PGD₂), a ligand for CRTH2, is produced from mast cellsand other important effector cells in allergic diseases (Nagata et al.,FEBS Lett., 459: 195-199, 1999; Hirai et al., J. Exp. Med., 193:255-261, 2001). The activation of CRTH2 by PGD₂ induces the migrationand activation of Th2 Cells and eosinophils, suggesting that CRTH2 mayplay a pro-inflammatory role in allergic diseases (Hirai et al., J. Exp.Med., 193: 255-261, 2001; Gervais et al., J. Allergy Clin. Immunol.,108: 982-988, 2001). Therefore, antagonists which inhibit the binding ofCRTH2 and PGD₂ should be useful for the treatment of allergic diseases,such as, asthma, exercise induced asthma, allergic rhinitis, atopicdermatitis and allergic conjuncitivitis.

In addition, experimental evidence has demonstrated the contribution ofeosinophils in sinusitis (Hamilos et al., Am. J. Respir. Cell and Mol.Biol., 15: 443-450, 1996; Fan et al., J. Allergy Clin. Immunol., 106:551-558, 2000), and Churg-Strauss syndrome (Coffin et al., J. AllergyClin. Immunol., 101: 116-123, 1998). In the tissues of these patients,mast cells can be observed to be colocalized with eosinophils (Khan etal., J. Allergy Clin. Immunol., 106: 1096: 1101, 2000). It is suggestedthat PGD₂ production from mast cells induces the recruitment ofeosinophils. Therefore, CRTH2 antagonists are also useful for thetreatment of other eosinophil-related diseases such as Churg-Strausssyndrome and sinusitis. CRTH2 antagonists can be useful for thetreatment of some basophil-related diseases such as basophilic leukemia,chronic urticaria and basophilic leukocytosis, because of the highexpression of CRTH2 on basophils.

Thus, there is a need for the development of compounds with CRTH2antagonistic activity for the treatment of CRTH2-mediated disorders ordiseases.

SUMMARY OF THE INVENTION

Provided herein are 2-S-benzyl pyrimidine compounds that are CRTH2antagonists, pharmaceutical compositions containing the compounds andmethods of use thereof. In certain embodiments, the compounds for use inthe compositions and methods provided herein are of the formula:

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer ortautomer thereof, wherein the variables are chosen such that theresulting compound shows activity as a CRTH2 antagonist.

Pharmaceutical compositions containing a compound of the formula aboveand a pharmaceutically acceptable carrier or excipient are providedherein. Also provided are methods for treating CRTH2 mediated diseasesor symptoms thereof by administering the compounds and compositionsprovided herein.

In certain embodiments, provided herein are methods for modulating anaction of CRTH2 receptor by contacting the receptor with a compound orcomposition provided herein. In one embodiment, provided herein aremethods for antagonizing an action of CRTH2 receptor by contacting thereceptor with a compound or composition provided herein. In anotherembodiment, provided herein are methods for treatment of one or moresymptoms of diseases or conditions associated with CRTH2 receptoractivity, including, but not limited to an allergic disease, aneosinophil-related disease, a basophil-related disease, or aninflammatory disease. In other embodiments, provided herein are methodsfor treating a disease or condition, or symptom thereof, wherein thedisease or condition is selected from the group consisting of asthma,exercise induced asthma, allergic rhinitis, atopic dermatitis, allergicconjunctivitis, Churg-Strauss syndrome, sinusitis, basophilic leukemia,chronic urticaria, basophilic leukocytosis, psoriasis, eczema,inflammatory bowel disease, ulcerative colitis, Crohn's disease, COPD(chronic obstructive pulmonary disorder) and arthritis.

DETAILED DESCRIPTION Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art to which this invention belongs. All patents, applications,published applications and other publications are incorporated byreference in their entirety. In the event that there are a plurality ofdefinitions for a term herein, those in this section prevail unlessstated otherwise.

As used herein, pharmaceutically acceptable derivatives of a compoundinclude salts, esters, enol ethers, enol esters, acetals, ketals,orthoesters, hemiacetals, hemiketals, solvates, hydrates or prodrugsthereof. Such derivatives may be readily prepared by those of skill inthis art using known methods for such derivatization. The compoundsproduced may be administered to animals or humans without substantialtoxic effects and either are pharmaceutically active or are prodrugs.

Pharmaceutically acceptable salts include, but are not limited to, aminesalts, such as but not limited to N,N′-dibenzylethylenediamine,chloroprocaine, choline, ammonia, diethanolamine and otherhydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine,N-benzylphenethylamine,1-para-chlorobenzyl-2-pyrrolidin-1′-ylmethyl-benzimidazole, diethylamineand other alkylamines, piperazine and tris(hydroxymethyl)aminomethane;alkali metal salts, such as but not limited to lithium, potassium andsodium; alkali earth metal salts, such as but not limited to barium,calcium and magnesium; transition metal salts, such as but not limitedto zinc; and other metal salts, such as but not limited to sodiumhydrogen phosphate and disodium phosphate; and also including, but notlimited to, salts of mineral acids, such as but not limited tohydrochlorides and sulfates; and salts of organic acids, such as but notlimited to acetates, lactates, malates, tartrates, citrates, ascorbates,succinates, butyrates, valerates and fumarates.

Pharmaceutically acceptable salts of the compounds provided herein alsoinclude the acid and base salts thereof.

Suitable acid salts are formed from acids which form non-toxic salts.Examples include, but are not limited to, the acetate, adipate,aspartate, benzoate, besylate, bicarbonate/carbonate,bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate,esylate, formate, fumarate, gluceptate, gluconate, glucuronate,hexafluorophosphate, hibenzate, hydrochloride/chloride,hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate,maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate,nicotinate, nitrate, orotate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate,saccharate, stearate, succinate, tannate, tartrate, tosylate,trifluoroacetate and xinofoate salts.

Suitable base salts are formed from bases which form non-toxic salts.Examples include the aluminum, arginine, benzathine, calcium, choline,diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine,potassium, sodium, tromethamine and zinc salts.

For a review on suitable salts, see Handbook of Pharmaceutical Salts:Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002).

Pharmaceutically acceptable esters include, but are not limited to,alkyl, alkenyl, alkynyl, aryl, aralkyl and cycloalkyl esters of acidicgroups, including, but not limited to, carboxylic acids, phosphoricacids, phosphinic acids, sulfonic acids, sulfinic acids and boronicacids. Pharmaceutically acceptable enol ethers include, but are notlimited to, derivatives of the formula C═C(OR) where R is hydrogen,alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl,cycloalkyl or heterocyclyl. Pharmaceutically acceptable enol estersinclude, but are not limited to, derivatives of formula C═C(OC(O)R)where R is hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl orcycloalkyl. Pharmaceutically acceptable solvates and hydrates arecomplexes of a compound with one or more solvent or water molecules, or1 to about 100, or 1 to about 10, or one to about 2, 3 or 4, solvent orwater molecules.

As used herein, the term “solvate” describes a molecular complexcomprising the compound of the invention and one or morepharmaceutically acceptable solvent molecules, for example, ethanol. Theterm “hydrate” is employed when said solvent is water.

As used herein, treatment means any manner in which one or more of thesymptoms of a disease or disorder are ameliorated or otherwisebeneficially altered. Treatment also encompasses any pharmaceutical useof the compositions herein, such as use for treating a CTRH2 mediateddisease or disorder, or diseases or disorders, in which CRTH2 activityis implicated.

As used herein, IC₅₀ refers to an amount, concentration or dosage of aparticular test compound that achieves a 50% inhibition of a maximalresponse, such as modulation of CRTH2 activity, in an assay thatmeasures such response.

It is to be understood that the compounds provided herein may containchiral centers. Such chiral centers may be of either the (R) or (S)configuration, or may be a mixture thereof. Thus, the compounds providedherein may be enantiomerically pure, or be stereoisomeric ordiastereomeric mixtures. In the case of amino acid residues, suchresidues may be of either the L- or D-form. The configuration fornaturally occurring amino acid residues is generally L. When notspecified, the residue is the L form. As used herein, the term “aminoacid” refers to α-amino acids which are racemic, or of either the D- orL-configuration. The designation “d” preceding an amino acid designation(e.g., dAla, dSer, dVal, etc.) refers to the D-isomer of the amino acid.The designation “dl” preceding an amino acid designation (e.g., dlPip)refers to a mixture of the D- and L-isomers of the amino acid. It is tobe understood that the chiral centers of the compounds provided hereinmay undergo epimerization in vivo. As such, one of skill in the art willrecognize that administration of a compound in its (R) form isequivalent, for compounds that undergo epimerization in vivo, toadministration of the compound in its (S) form.

As used herein, substantially pure means sufficiently homogeneous toappear free of readily detectable impurities as determined by standardmethods of analysis, such as thin layer chromatography (TLC), gelelectrophoresis, high performance liquid chromatography (HPLC) and massspectrometry (MS), used by those of skill in the art to assess suchpurity, or sufficiently pure such that further purification would notdetectably alter the physical and chemical properties, such as enzymaticand biological activities, of the substance. Methods for purification ofthe compounds to produce substantially chemically pure compounds areknown to those of skill in the art. A substantially chemically purecompound may, however, be a mixture of stereoisomers. In such instances,further purification might increase the specific activity of thecompound.

As used herein, the term “in combination with” means the administrationof a compound provided herein with one or more therapeutic agents eithersimultaneously, concurrently or sequentially with no specific timelimits. In one embodiment, the compound provided herein and theadditional agent or agents are present in the cell or in the subject'sbody at the same time or exert their biological or therapeutic effect atthe same time. In one embodiment, the compound provided herein and theadditional agent or agents are in the same composition or unit dosageform. In another embodiment, the compound provided herein and theadditional agent or agents are in separate compositions or unit dosageforms. In some embodiments, a first compound or agent can beadministered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequentto (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or12 weeks after) the administration of a second compound or agent.

As used herein, “isotopic composition” refers to the amount of eachisotope present for a given atom, and “natural isotopic composition”refers to the naturally occurring isotopic composition or abundance fora given atom. Atoms containing their natural isotopic composition mayalso be referred to herein as “non-enriched” atoms. Unless otherwisedesignated, the atoms of the compounds recited herein are meant torepresent any stable isotope of that atom. For example, unless otherwisestated, when a position is designated specifically as “H” or “hydrogen”,the position is understood to have hydrogen at its natural isotopiccomposition.

As used herein, “isotopically enriched” refers to an atom having anisotopic composition other than the natural isotopic composition of thatatom. “Isotopically enriched” may also refer to a compound containing atleast one atom having an isotopic composition other than the naturalisotopic composition of that atom.

As used herein, “isotopic enrichment” refers to the percentage ofincorporation of an amount of a specific isotope at a given atom in amolecule in the place of that atom's natural isotopic abundance. Forexample, deuterium enrichment of 1% at a given position means that 1% ofthe molecules in a given sample contain deuterium at the specifiedposition. Because the naturally occurring distribution of deuterium isabout 0.0156%, deuterium enrichment at any position in a compoundsynthesized using non-enriched starting materials is about 0.0156%. Theisotopic enrichment of the compounds provided herein can be determinedusing conventional analytical methods known to one of ordinary skill inthe art, including mass spectrometry and nuclear magnetic resonancespectroscopy.

As used herein, alkyl, alkenyl and alkynyl carbon chains, if notspecified, contain from 1 to 20 carbons, or 1 or 2 to 16 carbons, andare straight or branched. Alkenyl carbon chains of from 2 to 20 carbons,in certain embodiments, contain 1 to 8 double bonds and alkenyl carbonchains of 2 to 16 carbons, in certain embodiments, contain 1 to 5 doublebonds. Alkynyl carbon chains of from 2 to 20 carbons, in certainembodiments, contain 1 to 8 triple bonds, and the alkynyl carbon chainsof 2 to 16 carbons, in certain embodiments, contain 1 to 5 triple bonds.Exemplary alkyl, alkenyl and alkynyl groups herein include, but are notlimited to, methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl,sec-butyl, tert-butyl, isopentyl, neopentyl, tert-pentyl, isohexyl,allyl (propenyl) and propargyl (propynyl). As used herein, lower alkyl,lower alkenyl, and lower alkynyl refer to carbon chains having fromabout 1 or about 2 carbons up to about 6 carbons. As used herein,“alk(en)(yn)yl” refers to an alkyl group containing at least one doublebond and at least one triple bond.

As used herein, “cycloalkyl” refers to a saturated mono- or multi-cyclicring system, in certain embodiments of 3 to 10 carbon atoms, in otherembodiments of 3 to 6 carbon atoms; cycloalkenyl and cycloalkynyl referto mono- or multicyclic ring systems that respectively include at leastone double bond and at least one triple bond. Cycloalkenyl andcycloalkynyl groups may, in certain embodiments, contain 3 to 10 carbonatoms, with cycloalkenyl groups, in further embodiments, containing 4 to7 carbon atoms and cycloalkynyl groups, in further embodiments,containing 8 to 10 carbon atoms. The ring systems of the cycloalkyl,cycloalkenyl and cycloalkynyl groups may be composed of one ring or twoor more rings which may be joined together in a fused, bridged orspiro-connected fashion. “Cycloalk(en)(yn)yl” refers to a cycloalkylgroup containing at least one double bond and at least one triple bond.

As used herein, “aryl” refers to aromatic monocyclic or multicyclicgroups containing from 6 to 19 carbon atoms. Aryl groups include, butare not limited to groups such as unsubstituted or substitutedfluorenyl, unsubstituted or substituted phenyl, and unsubstituted orsubstituted naphthyl.

As used herein, “heteroaryl” refers to a monocyclic or multicyclicaromatic ring system, in certain embodiments, of about 5 to about 15members where one or more, in one embodiment 1 to 3, of the atoms in thering system is a heteroatom, that is, an element other than carbon,including but not limited to, nitrogen, oxygen or sulfur. The heteroarylgroup may be optionally fused to a benzene ring. Heteroaryl groupsinclude, but are not limited to, furyl, imidazolyl, pyrimidinyl,tetrazolyl, thienyl, pyridyl, pyrrolyl, thiazolyl, isothiazolyl,oxazolyl, isoxazolyl, triazolyl, quinolinyl and isoquinolinyl.

As used herein, “heterocyclyl” refers to a monocyclic or multicyclicnon-aromatic ring system, in one embodiment of 3 to 10 members, inanother embodiment of 4 to 7 members, in a further embodiment of 5 to 6members, where one or more, in certain embodiments, 1 to 3, of the atomsin the ring system is a heteroatom, that is, an element other thancarbon, including but not limited to, nitrogen, oxygen or sulfur. Inembodiments where the heteroatom(s) is(are) nitrogen, the nitrogen isoptionally substituted with alkyl, alkenyl, alkynyl, aryl, heteroaryl,aralkyl, heteroaralkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl,heterocyclylalkyl, acyl, guanidino, or the nitrogen may be quaternizedto form an ammonium group where the substituents are selected as above.

As used herein, “aralkyl” refers to an alkyl group in which one of thehydrogen atoms of the alkyl is replaced by an aryl group.

As used herein, “heteroaralkyl” refers to an alkyl group in which one ofthe hydrogen atoms of the alkyl is replaced by a heteroaryl group.

As used herein, “halo”, “halogen” or “halide” refers to F, Cl, Br or I.

As used herein, “haloalkyl” refers to an alkyl group in which one ormore of the hydrogen atoms are replaced by halogen. Such groups include,but are not limited to, chloromethyl, trifluoromethyl and1-chloro-2-fluoroethyl.

As used herein, “haloalkoxy” refers to RO— in which R is a haloalkylgroup.

As used herein, “sulfinyl” or “thionyl” refers to —S(O)—.

As used herein, “sulfonyl” refers to —S(O)₂—.

As used herein, “sulfamoyl” refers to —S(O)₂NR₂ in which each R isindependently hydrogen, aryl or alkyl, including lower alkyl.

As used herein, “carboxy” refers to —C(O)OH.

As used herein, “aminocarbonyl” or “carbamoyl” refers to —C(O)NH₂.

As used herein, “alkylaminocarbonyl” or “alkylcarbamoyl” refers to—C(O)NHR in which R is alkyl, including lower alkyl.

As used herein, “dialkylaminocarbonyl” or “dialkylcarbamoyl” refers to—C(O)NR′R in which R′ and R are independently alkyl, including loweralkyl; “carboxamide” refers to groups of formula —NR′COR in which R′ andR are independently alkyl, including lower alkyl.

As used herein, “cycloalkylaminocarbonyl” or “cycloalkylcarbamoyl”refers to —C(O)NHR in which R is cycloalkyl.

As used herein, “heterocyclylaminocarbonyl” or “heterocyclylcarbamoyl”refers to —C(O)NHR in which R is heterocyclyl.

As used herein, “alkoxy” and “alkylthio” refer to RO— and RS—, in whichR is alkyl, including lower alkyl.

As used herein, “aryloxy” and “arylthio” refer to RO— and RS—, in whichR is aryl, including lower aryl, such as phenyl.

As used herein, “alkylene” refers to a straight, branched or cyclic, incertain embodiments straight or branched, divalent aliphatic hydrocarbongroup, in one embodiment having from 1 to about 20 carbon atoms, inanother embodiment having from 1 to 12 carbons. In a further embodimentalkylene includes lower alkylene. There may be optionally inserted alongthe alkylene group one or more oxygen, sulfur, including S(═O) andS(═O)₂ groups, or substituted or unsubstituted nitrogen atoms, including—NR— and —N⁺RR— groups, where the nitrogen substituent(s) is(are) alkyl,aryl, aralkyl, heteroaryl, heteroaralkyl or COR′, where R′ is alkyl,aryl, aralkyl, heteroaryl, heteroaralkyl, —OY or —NYY, where Y ishydrogen, alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl. Alkylenegroups include, but are not limited to, methylene (—CH₂—), ethylene(—CH₂CH₂—), propylene (—(CH₂)₃—), methylenedioxy (—O—CH₂—O—) andethylenedioxy (—O—(CH₂)₂—O—). The term “lower alkylene” refers toalkylene groups having 1 to 6 carbons. In certain embodiments, alkylenegroups are lower alkylene, including alkylene of 1 to 3 carbon atoms.

As used herein, “amido” refers to the divalent group —C(O)NH—.“Thioamido” refers to the divalent group —C(S)NH—. “Oxyamido” refers tothe divalent group —OC(O)NH—. “Thiaamido” refers to the divalent group—SC(O)NH—. “Dithiaamido” refers to the divalent group —SC(S)NH—.“Ureido” refers to the divalent group —HNC(O)NH—. “Thioureido” refers tothe divalent group —HNC(S)NH—.

Where the number of any given substituent is not specified (e.g.,haloalkyl), there may be one or more substituents present. For example,“haloalkyl” may include one or more of the same or different halogens.As another example, “C₁₋₃alkoxyphenyl” may include one or more of thesame or different alkoxy groups containing one, two or three carbons.

As used herein, “alkyl,” “alkenyl,” “alkynyl,” “cycloalkyl,” “aryl,”“heteroaryl,” “heterocyclyl,” “aralkyl,” “heteroaralkyl,” “haloalkyl,”“haloalkoxy,” “carboxy,” “aminocarbonyl,” “carbamoyl”“alkylaminocarbonyl,” “alkylcarbamoyl,” “dialkylaminocarbonyl,”“dialkylcarbamoyl,” “cycloalkylaminocarbonyl,” “cycloalkylcarbamoyl,”“heterocyclylaminocarbonyl,” “heterocyclylcarbamoyl,” “alkoxy,”“alkylthio,” “aryloxy,” “arylthio,” “alkylene,” “amido,” “thioamido,”“oxyamido,” “thiaamido,” “dithiaamido,” “ureido” and “thioureido” groupsoptionally comprise deuterium at one or more positions where hydrogenatoms are present, and wherein the deuterium composition of the atom oratoms is other than the natural isotopic composition.

Also as used herein, “alkyl,” “alkenyl,” “alkynyl,” “cycloalkyl,”“aryl,” “heteroaryl,” “heterocyclyl,” “alkyl,” “alkenyl,” “alkynyl,”“cycloalkyl,” “aryl,” “heteroaryl,” “heterocyclyl,” “aralkyl,”“heteroaralkyl,” “haloalkyl,” “haloalkoxy,” “carboxy,” “aminocarbonyl,”“carbamoyl” “alkylaminocarbonyl,” “alkylcarbamoyl,”“dialkylaminocarbonyl,” “dialkylcarbamoyl,” “cycloalkylaminocarbonyl,”“cycloalkylcarbamoyl,” “heterocyclylaminocarbonyl,”“heterocyclylcarbamoyl,” “alkoxy,” “alkylthio,” “aryloxy,” “arylthio,”“alkylene,” “amido,” “thioamido,” “oxyamido,” “thiaamido,”“dithiaamido,” “ureido” and “thioureido” groups optionally comprisecarbon-13 at an amount other than the natural isotopic composition.

As used herein, the abbreviations for any protective groups, amino acidsand other compounds, are, unless indicated otherwise, in accord withtheir common usage, recognized abbreviations, or the IUPAC-IUBCommission on Biochemical Nomenclature (see, (1972) Biochem.11:942-944).

Compounds

In certain embodiments, the compounds for use in the compositions andmethods provided herein have Formula I:

-   -   or a pharmaceutically acceptable salt, solvate, hydrate,        stereoisomer or tautomer thereof, wherein

R¹ is —CO₂R⁹, —C(O)NR^(8a)R^(8b), (nitrile or tetrazolyl;

R^(4a) and R^(4b) are each independently hydrogen or (C₁-C₆)alkyl;

-   -   in each instance, independently, W, R², R³, R⁵, R^(5a), R⁶, R⁷,        R^(8a), R^(8b), R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, m and n are        selected from (I) or (II) as follows:        -   (I) W is a single bond, —(CH₂)_(m)—, —O—, —S(O)_(n)—, —NR⁷—,            —C(O)—, —C(O)O—, —C(O)NR⁷—, —NR⁷C(O)NR⁷— or —NR⁷C(O)O—;            -   in each instance, independently, R² and R³ are selected                from (i) or (ii) as follows:            -   (i) R² and R³ are each independently (a) hydrogen; (b)                F; (c) Br; (d) I; (e) (C₁-C₆)alkyl; (f) (C₁-C₆)alkyl                substituted by aryl, hydroxy, carboxy, alkoxy,                carbamoyl, (C₁-C₆)alkylcarbamoyl,                di(C₁-C₆)alkyl)carbamoyl, (C₃-C₇)cycloalkylcarbamoyl or                (C₃-C₇)heterocyclylcarbamoyl;                -   (g) (C₁-C₆)alkyl substituted by mono-, di-, or                    tri-halogen;                -   (h) (C₃-C₇)cycloalkyl; (i) —SR⁹; (j) —NR¹⁰R¹¹;                    or (k) (C₁-C₆)alkoxy optionally substituted by                    mono-, di-, or tri-halogen; or            -   (ii) R² and R³ are each independently (a) hydrogen; (b)                Cl; (c) (C₁-C₆)alkyl; (d) (C₁-C₆)alkyl substituted by                aryl, hydroxy, carboxy, alkoxy, carbamoyl,                (C₁-C₆)alkylcarbamoyl, di(C₁-C₆)alkyl)carbamoyl,                (C₃-C₇)cycloalkylcarbamoyl or                (C₃-C₇)heterocyclylcarbamoyl;                -   (e) (C₁-C₆)alkyl substituted by mono-, di-, or                    tri-halogen;                -   (f) (C₃-C₇)cycloalkyl; (g) —SR⁹; (h) —NR¹²R¹³;                    or (i) (C₁-C₆)alkoxy optionally substituted by                    mono-, di-, or tri-halogen;            -   R⁵ is (a) hydrogen; (b) halogen; (c) cyano; (d)                nitro; (e) hydroxy; (f) phenyl; (g) phenyloxy; (h)                benzyl; (i) benzyloxy; (j) guanidino; (k)                heterocyclyl; (l) —NR¹⁴R¹⁵;                -   (m) sulfamoyl; (n) (C₁-C₆)alkylsulfonyl;                -   (O) (C₁-C₆)alkylaminosulfonyl; (p)                    di(C₁-C₆)alkylaminosulfonyl;                -   (q) —C(O)R⁹; (r) —C(O)OR⁹; (s)                    —C(O)NR^(8a)R^(8b); (t) —NR⁷C(O)R⁹;                -   (u) —OC(O)NR^(8a)R^(8b); (v) —NR⁷C(O)OR⁹; (w)                    (C₂-C₆)alkenyl; (x) (C₁-C₆)alkyl optionally                    substituted by mono-, di-, or tri-halogen;                -   (y) (C₁-C₆)alkoxy optionally substituted by mono-,                    di-, or tri-halogen; or (z) (C₁-C₆)alkylthio                    optionally substituted by mono-, di-, or                    tri-halogen;            -   R⁶ is (a) hydrogen; (b) (C₁-C₆)alkyl; (c)                (C₂-C₆)alkenyl;                -   (d) (C₂-C₆)alkynyl; (e) (C₃-C₇)cycloalkyl; (f)                    (C₁-C₆)alkyl substituted by aryl or heteroaryl; (g)                    (C₂-C₄)alkenyl substituted by aryl or                    heteroaryl; (h) (C₁-C₆)alkyl substituted by mono-,                    di-, or tri-halogen; (i) (C₁-C₆)alkyl substituted by                    —C(O)R^(6a); (j) (C₁-C₆)alkoxy substituted by mono-,                    di-, or tri-halogen; (k) (C₁-C₆)alkylthio                    substituted by mono-, di-, or tri-halogen; (l)                    aryl; (m) or heteroaryl, wherein said aryl and                    heteroaryl are optionally substituted at a                    substitutable position with one or more substituents                    selected from the group consisting of (a)                    halogen; (b) cyano; (c) nitro; (d) hydroxy; (e)                    guanidino; (f) heterocyclyl; (g) phenyl; (h)                    phenyloxy; (i) benzyl; (j) benzyloxy; (k)                    —NR^(8a)R^(8b); (l) —C(O)R⁹; (m)                    —C(O)NR^(8a)R^(8b); (n) —OC(O)NR^(8a)R^(8b); (O)                    —C(O)OR⁹; (p) —NR⁷C(O)OR⁹; (q) —NR⁷C(O)R⁹; (r)                    sulfamoyl; (s) (C₁-C₆)alkylsulfonyl; (t)                    (C₁-C₆)alkylaminosulfonyl;                -   (u) di(C₁-C₆)alkylaminosulfonyl; (v) (C₁-C₆)alkyl                    optionally substituted by mono-, di-, or                    tri-halogen; (w) (C₁-C₆)alkoxy optionally                    substituted by mono-, di-, or tri-halogen; and (x)                    (C₁-C₆)alkylthio optionally substituted by mono-,                    di-, or tri-halogen;            -   R^(6a) is (a) hydrogen; (b) (C₁-C₆)alkyl; (c)                (C₂-C₆)alkenyl;                -   (d) (C₂-C₆)alkynyl; (e) (C₃-C₇)cycloalkyl; (f)                    (C₁-C₆)alkyl substituted by aryl or heteroaryl; (g)                    (C₂-C₄)alkenyl substituted by aryl or                    heteroaryl; (h) (C₁-C₆)alkyl substituted by mono-,                    di-, or tri-halogen; (i) (C₁-C₆)alkoxy substituted                    by mono-, di-, or tri-halogen; (j) (C₁-C₆)alkylthio                    substituted by mono-, di-, or tri-halogen; (k)                    aryl; (l) or heteroaryl, wherein said aryl and                    heteroaryl are optionally substituted at a                    substitutable position with one or more substituents                    selected from the group consisting of (a)                    halogen; (b) cyano; (c) nitro; (d) hydroxy; (e)                    guanidino; (0 heterocyclyl; (g) phenyl; (h)                    phenyloxy; (i) benzyl; (j) benzyloxy; (k)                    —NR^(8a)R^(8b); (l) —C(O)R⁹; (m)                    —C(O)NR^(8a)R^(8b); (n) —OC(O)NR^(8a)R^(8b);                    (o)—C(O)OR⁹; (p) —NR⁷C(O)OR⁹;                -   (q) —NR⁷C(O)R⁹; (r) sulfamoyl; (s)                    (C₁-C₆)alkylsulfonyl;                -   (t) (C₁-C₆)alkylaminosulfonyl; (u)                    di(C₁-C₆)alkylaminosulfonyl;                -   (v) (C₁-C₆)alkyl optionally substituted by mono-,                    di-, or tri-halogen;                -   (w) (C₁-C₆)alkoxy optionally substituted by mono-,                    di-, or tri-halogen; and (x) (C₁-C₆)alkylthio                    optionally substituted by mono-, di-, or                    tri-halogen;            -   R⁷ is (a) hydrogen; (b) (C₁-C₆)alkyl; (c) phenyl; (d)                (C₁-C₆)alkyl substituted by aryl, hydroxy, carboxy,                alkoxy, carbamoyl, (C₁-C₆)alkylcarbamoyl,                di((C₁-C₆)alkyl)carbamoyl, (C₃-C₇)cycloalkylcarbamoyl or                (C₃-C₇)heterocyclylcarbamoyl;                -   (e) (C₁-C₆)alkyl substituted by mono-, di-, or                    tri-halogen; or                -   (f) (C₃-C₇)cycloalkyl;            -   in each instance, independently, R^(8a) and R^(8b) are                selected from (i) or (ii) as follows:                -   (i) R^(8a) and R^(8b) are each independently                    selected from (a) hydrogen; (b) (C₁-C₆)alkyl; (c)                    phenyl; (d) (C₁-C₆)alkyl substituted by aryl,                    hydroxy, carboxy, alkoxy, carbamoyl,                    (C₁-C₆)alkylcarbamoyl, di((C₁-C₆)alkyl)carbamoyl,                    (C₃-C₇)cycloalkylcarbamoyl or                    (C₃-C₇)heterocyclylcarbamoyl; (e) (C₁-C₆)alkyl                    substituted by mono-, di-, or tri-halogen; or (f)                    (C₃-C₇)cycloalkyl; or                -   (ii) each R^(8a) and R^(8b), together with the N to                    which they are bonded, independently may form a 3 to                    8 membered saturated or unsaturated ring optionally                    containing one or more O or S atoms, or one or more                    additional N atoms, in the ring;            -   each R⁹ is independently (a) hydrogen; (b) (C₁-C₆)alkyl;                phenyl; or (c) (C₁-C₆)alkyl substituted by aryl, alkoxy                or mono-, di-, or tri-halogen;            -   in each instance, independently, R¹⁰ and R¹¹ are                selected from (i) or (ii) as follows:                -   (i) R¹⁰ and R¹¹ are each independently selected                    from (a) hydrogen; (b) (C₁-C₆)alkyl; (c) phenyl; (d)                    (C₁-C₆)alkyl substituted by aryl, hydroxy, carboxy,                    alkoxy, carbamoyl, (C₁-C₆)alkylcarbamoyl,                    di((C₁-C₆)alkyl)carbamoyl,                    (C₃-C₇)cycloalkylcarbamoyl or                    (C₃-C₇)heterocyclylcarbamoyl; (e) (C₁-C₆)alkyl                    substituted by mono-, di-, or tri-halogen; or (f)                    (C₃-C₇)cycloalkyl; or                -   (ii) each R¹⁰ and R¹¹, together with the N to which                    they are bonded, independently may form a 3 to 8                    membered saturated or unsaturated ring optionally                    containing one or more O or S atoms, or one or more                    additional N atoms, in the ring;            -   in each instance, independently, R¹² and R¹³ are                selected from (i), (ii), (iii) or (iv) as follows:                -   (i) R¹² and R¹³ are each independently selected                    from (a) hydrogen; (b) (C₁-C₆)alkyl; (c) phenyl; (d)                    (C₁-C₆)alkyl substituted by aryl, hydroxy, carboxy                    or alkoxy; (e) (C₁-C₆)alkyl substituted by mono-,                    di-, or tri-halogen; or (t) (C₃-C₇)cycloalkyl;                -   (ii) R¹² and R¹³, together with the N to which they                    are bonded, form a 5 membered saturated ring                    containing at least one O or S atom, or at least one                    additional N atom, in the ring;                -   (iii)R¹² and R¹³, together with the N to which they                    are bonded, form a 5 membered unsaturated ring,                    optionally containing one or more O or S atom, or                    one or more additional N atoms, in the ring; or                -   (iv) R¹² and R¹³, together with the N to which they                    are bonded, form a 3, 4, 6, 7 or 8 membered                    saturated or unsaturated ring, optionally containing                    one or more O or S atoms, or one or more additional                    N atoms, in the ring;            -   in each instance, independently, R¹⁴ and R¹⁵ are                selected from (i) or (ii) as follows:                -   (i) R¹⁴ and R¹⁵ are each independently selected                    from (a) hydrogen; (b) (C₁-C₆)alkyl; (c) phenyl; (d)                    (C₁-C₆)alkyl substituted by aryl, hydroxy, carboxy,                    alkoxy, carbamoyl, (C₁-C₆)alkylcarbamoyl,                    di((C₁-C₆)alkyl)carbamoyl,                    (C₃-C₇)cycloalkylcarbamoyl or                    (C₃-C₇)heterocyclylcarbamoyl; (e) (C₁-C₆)alkyl                    substituted by mono-, di-, or tri-halogen; or (f)                    (C₃-C₇)cycloalkyl; or                -   (ii) each R¹⁴ and R¹⁵, together with the N to which                    they are bonded, independently may form a 3 to 8                    membered saturated or unsaturated ring optionally                    containing one or more O or S atoms, or one or more                    additional N atoms, in the ring;            -   k is 0, 1 or 2;            -   m is 1, 2, 3 or 4;            -   n is 0, 1 or 2; or        -   (II) R⁵ and W—R⁶ together with the atom to which they are            attached may form a 4 to 8 membered unsaturated ring            optionally containing one or more N, O or S atoms in the            ring, wherein the ring is optionally substituted with one or            more R^(5a) groups;            -   R² and R³ are each independently (a) hydrogen; (b)                F; (c) (d) Br; (e) I; (f) (C₁-C₆)alkyl; (g) (C₁-C₆)alkyl                substituted by aryl, hydroxy, carboxy, alkoxy,                carbamoyl, (C₁-C₆)alkylcarbamoyl,                di(C₁-C₆)alkyl)carbamoyl, (C₃-C₇)cycloalkylcarbamoyl or                (C₃-C₇)heterocyclylcarbamoyl; (h) (C₁-C₆)alkyl                substituted by mono-, di-, or tri-halogen; (i)                (C₃-C₇)cycloalkyl; (j) —SR⁹; (k) —NR¹⁰R¹¹; or (l)                (C₁-C₆)alkoxy optionally substituted by mono-, di-, or                tri-halogen;            -   R⁵ and R^(5a) are each independently (a) hydrogen; (b)                halogen; (c) cyano; (d) nitro; (e) hydroxy; (l)                phenyl; (g) phenyloxy; (h) benzyl; (i) benzyloxy; (j)                guanidino; (k) heterocyclyl; (l) —NR¹⁴R¹⁵; (m)                sulfamoyl; (n) (C₁-C₆)alkylsulfonyl; (o)                (C₁-C₆)alkylaminosulfonyl; (p)                di(C₁-C₆)alkylaminosulfonyl; (q) —C(O)R⁹; (r)                —C(O)OR⁹; (s) —C(O)NR^(8a)R^(8b); (t) —NR⁷C(O)R⁹; (u)                —OC(O)NR^(8a)R^(8b); (v) —NR⁷C(O)OR⁹; (w)                (C₂-C₆)alkenyl; (x) (C₁-C₆)alkyl optionally substituted                by mono-, di-, or tri-halogen; (y) (C₁-C₆)alkoxy                optionally substituted by mono-, di-, or tri-halogen;                or (z) (C₁-C₆)alkylthio optionally substituted by mono-,                di-, or tri-halogen;            -   R⁶ is (a) hydrogen; (b) (C₁-C₆)alkyl; (c)                (C₂-C₆)alkenyl; (d) (C₂-C₆)alkynyl; (e)                (C₃-C₇)cycloalkyl; (f) (C₁-C₆)alkyl substituted by aryl                or heteroaryl; (g) (C₂-C₄)alkenyl substituted by aryl or                heteroaryl; (h) (C₁-C₆)alkyl substituted by mono-, di-,                or tri-halogen; (i) (C₁-C₆)alkyl substituted by                —C(O)R^(6a); (j) (C₁-C₆)alkoxy substituted by mono-,                di-, or tri-halogen; (k) (C₁-C₆)alkylthio substituted by                mono-, di-, or tri-halogen; (l) aryl; (m) or heteroaryl,                wherein said aryl and heteroaryl are optionally                substituted at a substitutable position with one or more                substituents selected from the group consisting of (a)                halogen; (b) cyano; (c) nitro; (d) hydroxy; (e)                guanidino; (f) heterocyclyl; (g) phenyl; (h)                phenyloxy; (i) benzyl; (j) benzyloxy; (k)                —NR^(8a)R^(8b); (l) —C(O)R⁹; (m) —C(O)NR^(8a)R^(8b); (n)                —OC(O)NR^(8a)R^(8b); (o) —C(O)OR⁹; (p) —NR⁷C(O)OR⁹; (q)                —NR⁷C(O)R⁹; (r) sulfamoyl; (s) (C₁-C₆)alkylsulfonyl; (t)                (C₁-C₆)alkylaminosulfonyl;                -   (u) di(C₁-C₆)alkylaminosulfonyl; (v) (C₁-C₆)alkyl                    optionally substituted by mono-, di-, or                    tri-halogen; (w) (C₁-C₆)alkoxy optionally                    substituted by mono-, di-, or tri-halogen; and (x)                    (C₁-C₆)alkylthio optionally substituted by mono-,                    di-, or tri-halogen;            -   R^(6a) is (a) hydrogen; (b) (C₁-C₆)alkyl; (c)                (C₂-C₆)alkenyl;                -   (d) (C₂-C₆)alkynyl; (e) (C₃-C₇)cycloalkyl; (f)                    (C₁-C₆)alkyl substituted by aryl or heteroaryl; (g)                    (C₂-C₄)alkenyl substituted by aryl or                    heteroaryl; (h) (C₁-C₆)alkyl substituted by mono-,                    di-, or tri-halogen; (i) (C₁-C₆)alkoxy substituted                    by mono-, di-, or tri-halogen; (j) (C₁-C₆)alkylthio                    substituted by mono-, di-, or tri-halogen; (k)                    aryl; (l) or heteroaryl, wherein said aryl and                    heteroaryl are optionally substituted at a                    substitutable position with one or more substituents                    selected from the group consisting of (a)                    halogen; (b) cyano; (c) nitro; (d) hydroxy; (e)                    guanidino; (f) heterocyclyl; (g) phenyl; (h)                    phenyloxy; (i) benzyl; (j) benzyloxy; (k)                    —NR^(8a)R^(8b); (l) —C(O)R⁹; (m)                    —C(O)NR^(8a)R^(8b); (n) —OC(O)NR^(8a)R^(8b); (o)                    —C(O)OR⁹; (p) —NR⁷C(O)OR⁹;                -   (q) —NR⁷C(O)R⁹; (r) sulfamoyl; (s)                    (C₁-C₆)alkylsulfonyl;                -   (t) (C₁-C₆)alkylaminosulfonyl; (u)                    di(C₁-C₆)alkylaminosulfonyl;                -   (v) (C₁-C₆)alkyl optionally substituted by mono-,                    di-, or tri-halogen;                -   (w) (C₁-C₆)alkoxy optionally substituted by mono-,                    di-, or tri-halogen; and (x) (C₁-C₆)alkylthio                    optionally substituted by mono-, di-, or                    tri-halogen;            -   R⁷ is (a) hydrogen; (b) (C₁-C₆)alkyl; (c) phenyl; (d)                (C₁-C₆)alkyl substituted by aryl, hydroxy, carboxy,                alkoxy, carbamoyl, (C₁-C₆)alkylcarbamoyl,                di((C₁-C₆)alkyl)carbamoyl, (C₃-C₇)cycloalkylcarbamoyl or                (C₃-C₇)heterocyclylcarbamoyl; (e) (C₁-C₆)alkyl                substituted by mono-, di-, or tri-halogen; or (f)                (C₃-C₇)cycloalkyl;            -   in each instance, independently, R^(8a) and R^(8b) are                selected from (i) or (ii) as follows:                -   (i) R^(8a) and R^(8b) are each independently                    selected from (a) hydrogen; (b) (C₁-C₆)alkyl; (c)                    phenyl; (d) (C₁-C₆)alkyl substituted by aryl,                    hydroxy, carboxy, alkoxy, carbamoyl,                    (C₁-C₆)alkylcarbamoyl, di((C₁-C₆)alkyl)carbamoyl,                    (C₃-C₇)cycloalkylcarbamoyl or                    (C₃-C₇)heterocyclylcarbamoyl; (e) (C₁-C₆)alkyl                    substituted by mono-, di-, or tri-halogen; or (f)                    (C₃-C₇)cycloalkyl; or                -   (ii) each R^(8a) and R^(8b), together with the N to                    which they are bonded, independently may form a 3 to                    8 membered saturated or unsaturated ring optionally                    containing one or more O or S atoms, or one or more                    additional N atoms, in the ring;            -   each R⁹ is independently (a) hydrogen; (b) (C₁-C₆)alkyl;                phenyl; or (c) (C₁-C₆)alkyl substituted by aryl, alkoxy                or mono-, di-, or tri-halogen;            -   in each instance, independently, R¹⁰ and R¹¹ are                selected from (i) or (ii) as follows:                -   (i) R¹⁰ and R¹¹ are each independently selected                    from (a) hydrogen; (b) (C₁-C₆)alkyl; (c) phenyl; (d)                    (C₁-C₆)alkyl substituted by aryl, hydroxy, carboxy,                    alkoxy, carbamoyl, (C₁-C₆)alkylcarbamoyl,                    di((C₁-C₆)alkyl)carbamoyl,                    (C₃-C₇)cycloalkylcarbamoyl or                    (C₃-C₇)heterocyclylcarbamoyl; (e) (C₁-C₆)alkyl                    substituted by mono-, di-, or tri-halogen; or (f)                    (C₃-C₇)cycloalkyl; or                -   (ii) each R¹⁰ and R¹¹, together with the N to which                    they are bonded, independently may form a 3 to 8                    membered saturated or unsaturated ring optionally                    containing one or more O or S atoms, or one or more                    additional N atoms, in the ring;            -   k is 0, 1 or 2;            -   m is 1, 2, 3 or 4; and            -   n is 0, 1 or 2.

In one embodiment, in each instance, independently, R¹⁰ and R¹¹ areselected from (i) or (ii) as follows:

-   -   (i) R¹⁰ and R¹¹ are each independently selected from (a)        hydrogen; (b) (C₁-C₆)alkyl; (c) phenyl; (d) (C₁-C₆)alkyl        substituted by unsubstituted phenyl, hydroxy, carboxy, alkoxy,        carbamoyl, (C₁-C₆)alkylcarbamoyl, di((C₁-C₆)alkyl)carbamoyl,        (C₃-C₇)cycloalkylcarbamoyl or (C₃-C₇)heterocyclylcarbamoyl; (e)        (C₁-C₆)alkyl substituted by mono-, di-, or tri-halogen; or (f)        (C₃-C₇)cycloalkyl; or    -   (ii) each R¹⁰ and R¹¹, together with the N to which they are        bonded, independently may form a 3 to 8 membered saturated or        unsaturated ring optionally containing one or more O or S atoms,        or one or more additional N atoms, in the ring; and    -   in each instance, independently, R¹² and R¹³ are selected from        (i), (ii), (iii) or (iv) as follows:    -   (i) R¹² and R¹³ are each independently selected from (a)        hydrogen;        -   (b) (C₁-C₆)alkyl; (c) phenyl; (d) (C₁-C₆)alkyl substituted            by unsubstituted phenyl, hydroxy, carboxy or alkoxy; (e)            (C₁-C₆)alkyl substituted by mono-, di-, or tri-halogen;            or (f) (C₃-C₇)cycloalkyl;    -   (ii) R¹² and R¹³, together with the N to which they are bonded,        form a 5 membered saturated ring containing at least one O or S        atom, or at least one additional N atom, in the ring;    -   (iii) R¹² and R¹³, together with the N to which they are bonded,        form a 5 membered unsaturated ring, optionally containing one or        more O or S atom, or one or more additional N atoms, in the        ring; or    -   (iv) R¹² and R¹³, together with the N to which they are bonded,        form a 3, 4, 6, 7 or 8 membered saturated or unsaturated ring,        optionally containing one or more O or S atoms, or one or more        additional N atoms, in the ring.

In another embodiment, in each instance, independently, R¹⁰ and R¹¹ areselected from (i) or (ii) as follows:

-   -   (i) R¹⁰ and R¹¹ are each independently selected from (a)        hydrogen; (b) (C₁-C₆)alkyl; (c) phenyl; (d) (C₁-C₆)alkyl        substituted by hydroxy, carboxy, alkoxy, carbamoyl,        (C₁-C₆)alkylcarbamoyl, di((C₁-C₆)alkyl)carbamoyl,        (C₃-C₇)cycloalkylcarbamoyl or (C₃-C₇)heterocyclylcarbamoyl; (e)        (C₁-C₆)alkyl substituted by mono-, di-, or tri-halogen; or (f)        (C₃-C₇)cycloalkyl; or    -   (ii) each R¹⁰ and R¹¹, together with the N to which they are        bonded, independently may form a 3 to 8 membered saturated or        unsaturated ring optionally containing one or more O or S atoms,        or one or more additional N atoms, in the ring; and    -   in each instance, independently, R¹² and R¹³ are selected from        (i), (ii), (iii) or (iv) as follows:    -   (i) R¹² and R¹³ are each independently selected from (a)        hydrogen; (b) (C₁-C₆)alkyl; (c) phenyl; (d) (C₁-C₆)alkyl        substituted by hydroxy, carboxy or alkoxy; (e) (C₁-C₆)alkyl        substituted by mono-, di-, or tri-halogen; or (f)        (C₃-C₇)cycloalkyl;    -   (ii) R¹² and R¹³, together with the N to which they are bonded,        form a 5 membered saturated ring containing at least one O or S        atom, or at least one additional N atom, in the ring;    -   (iii) R¹² and R¹³, together with the N to which they are bonded,        form a 5 membered unsaturated ring, optionally containing one or        more O or S atom, or one or more additional N atoms, in the        ring; or    -   (iv) R¹² and R¹³, together with the N to which they are bonded,        form a 3, 4, 6, 7 or 8 membered saturated or unsaturated ring,        optionally containing one or more O or S atoms, or one or more        additional N atoms, in the ring.

In another embodiment, in each instance, independently, R¹⁰ and R¹¹ areselected from (i) or (ii) as follows:

-   -   (i) R¹⁰ and R¹¹ are each independently selected from (a)        hydrogen; (b) (C₁-C₆)alkyl; (c) phenyl; (d) (C₁-C₆)alkyl        substituted by mono-, di-, or tri-halogen; or (e)        (C₃-C₇)cycloalkyl; or    -   (ii) each R¹⁰ and R¹¹, together with the N to which they are        bonded, independently may form a 3 to 8 membered saturated or        unsaturated ring optionally containing one or more O or S atoms,        or one or more additional N atoms, in the ring; and    -   in each instance, independently, R¹² and R¹³ are selected from        (i), (ii), (iii) or (iv) as follows:    -   (i) R¹² and R¹³ are each independently selected from (a)        hydrogen; (b) (C₁-C₆)alkyl; (c) phenyl; (d) (C₁-C₆)alkyl        substituted by mono-, di-, or tri-halogen; or (e)        (C₃-C₇)cycloalkyl;    -   (ii) R¹² and R¹³, together with the N to which they are bonded,        form a 5 membered saturated ring containing at least one O or S        atom, or at least one additional N atom, in the ring;    -   (iii) R¹² and R¹³, together with the N to which they are bonded,        form a 5 membered unsaturated ring, optionally containing one or        more O or S atom, or one or more additional N atoms, in the        ring; or    -   (iv) R¹² and R¹³, together with the N to which they are bonded,        form a 3, 4, 6, 7 or 8 membered saturated or unsaturated ring,        optionally containing one or more O or S atoms, or one or more        additional N atoms, in the ring.

In one embodiment, R¹ is —CO₂H.

In another embodiment, R^(4a) and R^(4b) are each independentlyhydrogen.

In another embodiment, the compounds have formula II:

-   -   or a pharmaceutically acceptable salt, solvate, hydrate,        stereoisomer or tautomer thereof, wherein

X is a single bond, —O(CH₂)_(p)— or —NR⁹(CH₂)_(p)—;

R⁹ is hydrogen or (C₁-C₆)alkyl; and

p is 1, 2, 3, 4, 5 or 6.

In certain embodiments, R² is halogen.

In certain embodiments, R^(4a) and R^(4b) are each independentlyhydrogen.

In another embodiment, R⁶ is aryl or heteroaryl, wherein said aryl andheteroaryl are optionally substituted at a substitutable position withone or more substituents selected from the group consisting of (a)halogen; (b) cyano; (c) nitro; (d) hydroxy; (e) —NR¹⁴R¹⁵; (f) —C(O)R⁹;(g) —C(O)NR^(8a)R^(8b); (h) —NR⁷C(O)R⁹; (i) —OC(O)NR^(8a)R^(8b); (j)—NR⁷C(O)OR⁹; (k) —C(O)OR⁹; (l) guanidino; (m) heterocyclyl; (n) phenyl;(o) phenyloxy; (p) benzyl; (q) benzyloxy; (r) sulfamoyl; (s)(C₁-C₆)alkylsulfonyl; (t) (C₁-C₆)alkylaminosulfonyl; (u)di(C₁-C₆)alkylaminosulfonyl; (v) (C₁-C₆)alkyl optionally substituted bymono-, di-, or tri-halogen; (w) (C₁-C₆)alkoxy optionally substituted bymono-, di-, or tri-halogen; and (x) (C₁-C₆)alkylthio optionallysubstituted by mono-, di-, or tri-halogen;

R⁷ is hydrogen or (C₁-C₆)alkyl;

in each instance, independently, R^(8a) and R^(8b) are selected from (i)or (ii) as follows:

-   -   (i) R^(8a) and R^(8b), are each independently selected from        hydrogen or (C₁-C₆)alkyl; or    -   (ii) each R^(8a) and R^(8b), together with the N to which they        are bonded, independently may form a 3 to 8 membered saturated        or unsaturated ring optionally containing one or more O or S        atoms, or one or more additional N atoms, in the ring;

in each instance, independently, R¹⁴ and R¹⁵ are selected from (i) or(ii) as follows:

-   -   (i) R¹⁴ and R¹⁵ are each independently selected from (a)        hydrogen; (b) (C₁-C₆)alkyl; (c) phenyl; (d) (C₁-C₆)alkyl        substituted by aryl, hydroxy, carboxy or alkoxy; (e)        (C₁-C₆)alkyl substituted by mono-, di-, or tri-halogen; or (f)        (C₃-C₇)cycloalkyl; or    -   (ii) each R¹⁴ and R¹⁵, together with the N to which they are        bonded, independently may form a 3 to 8 membered saturated or        unsaturated ring optionally containing one or more O or S atoms,        or one or more additional N atoms, in the ring.

In one embodiment, the compounds for use in the compositions and methodsprovided herein have Formula III:

-   -   or a pharmaceutically acceptable salt, solvate, hydrate,        stereoisomer or tautomer thereof, wherein R⁹ is hydrogen.

In another embodiment, R⁶ is aryl or heteroaryl, wherein said aryl andheteroaryl are optionally substituted at a substitutable position withone or more substituents selected from the group consisting of (a)halogen; (b) cyano; (c) nitro; (d) hydroxy;

-   -   (e) —NR¹⁴R¹⁵; (f) —C(O)R⁹; (g) —C(O)NR^(8a)R^(8b); (h)        —NR⁷C(O)R⁹;    -   (i) —OC(O)NR^(8a)R^(8b); (j) —NR⁷C(O)OR⁹; (k) —C(O)OR⁹;    -   (l) guanidino; (m) heterocyclyl; (n) phenyl; (o) phenyloxy; (p)        benzyl;    -   (q) benzyloxy; (r) sulfamoyl; (s) (C₁-C₆)alkylsulfonyl;    -   (t) (C₁-C₆)alkylaminosulfonyl; (u) di(C₁-C₆)alkylaminosulfonyl;    -   (v) (C₁-C₆)alkyl optionally substituted by mono-, di-, or        tri-halogen;    -   (w) (C₁-C₆)alkoxy optionally substituted by mono-, di-, or        tri-halogen; and    -   (x) (C₁-C₆)alkylthio optionally substituted by mono-, di-, or        tri-halogen;

R⁷ is hydrogen or (C₁-C₆)alkyl;

in each instance, independently, R^(8a) and R^(8b) are selected from (i)or (ii) as follows:

-   -   (i) R^(8a) and R^(8b) are each independently selected from        hydrogen or (C₁-C₆)alkyl; or    -   (ii) each R^(8a) and R^(8b), together with the N to which they        are bonded, independently may form a 3 to 8 membered saturated        or unsaturated ring optionally containing one or more O or S        atoms, or one or more additional N atoms, in the ring;

in each instance, independently, R¹⁴ and R¹⁵ are selected from (i) or(ii) as follows:

-   -   (i) R¹⁴ and R¹⁵ are each independently selected from (a)        hydrogen; (b) (C₁-C₆)alkyl; (c) phenyl; (d) (C₁-C₆)alkyl        substituted by aryl, hydroxy, carboxy or alkoxy; (e)        (C₁-C₆)alkyl substituted by mono-, di-, or tri-halogen; or (f)        (C₃-C₇)cycloalkyl; or    -   (ii) each R¹⁴ and R¹⁵, together with the N to which they are        bonded, independently may form a 3 to 8 membered saturated or        unsaturated ring optionally containing one or more O or S atoms,        or one or more additional N atoms, in the ring.

In certain embodiments, R² and R³ are each —N(CH₃)₂.

In one embodiment, the compounds for use in the compositions and methodsprovided herein have formula IV:

-   -   or a pharmaceutically acceptable salt, solvate, hydrate,        stereoisomer or tautomer thereof, wherein

R² is halogen;

-   -   each R¹⁶ is independently (a) hydrogen (b) halogen; (c)        cyano; (d) nitro; (e) hydroxy; (f) —NR¹⁴R¹⁵; (g) —C(O)R⁹; (h)        —C(O)NR^(8a)R^(8b); (i) —NR⁷C(O)R⁹; (j) —OC(O)NR^(8a)R^(8b); (k)        —NR⁷C(O)OR⁹; (l) —C(O)OR⁹;        -   (m) guanidino; (n) heterocyclyl; (o) phenyl; (p)            phenyloxy; (q) benzyl;        -   (r) benzyloxy; (s) sulfamoyl; (t) (C₁-C₆)alkylsulfonyl;        -   (u) (C₁-C₆)alkylaminosulfonyl; (v)            di(C₁-C₆)alkylaminosulfonyl;        -   (w) (C₁-C₆)alkyl optionally substituted by mono-, di-, or            tri-halogen; (x) (C₁-C₆)alkoxy optionally substituted by            mono-, di-, or tri-halogen; and (y) (C₁-C₆)alkylthio            optionally substituted by mono-, di-, or tri-halogen; and

q is 0, 1, 2, 3, 4 or 5.

In certain embodiments, each R¹⁶ is independently (a) hydrogen (b)halogen; (c) cyano; (d) nitro; (e) hydroxy; (f) —NH₂; (g)—NH(C₁-C₆)alkyl; (h) —N((C₁-C₆)alkyl)₂; (i) —NHC(O)(C₁-C₆)alkyl; (j)—C(O)(C₁-C₆)alkyl; (k) —CO₂H; (l) —C(O)O(C₁-C₆)alkyl; (m) phenyl; (n)phenyloxy; (o) benzyl; (p) benzyloxy; (q) sulfamoyl; (r)(C₁-C₆)alkylsulfonyl; (s) (C₁-C₆)alkylaminosulfonyl; (t)di(C₁-C₆)alkylaminosulfonyl; (u) (C₁-C₆)alkyl optionally substituted bymono-, di-, or tri-halogen; (v) (C₁-C₆)alkoxy optionally substituted bymono-, di-, or tri-halogen; or (w) (C₁-C₆)alkylthio optionallysubstituted by mono-, di-, or tri-halogen.

In one embodiment, the compounds for use in the compositions and methodsprovided herein have formula V:

-   -   or a pharmaceutically acceptable salt, solvate, hydrate,        stereoisomer or tautomer thereof.

In certain embodiments, R² is halogen.

In certain embodiments, R² is halogen and R³ is —N(CH₃)₂.

In another embodiment, R² and R³ are each independently —N(CH₃)₂.

In one embodiment, the compound has formula:

In another embodiment, the compound has formula:

In another embodiment, the compound has formula:

In another embodiment, the compound has formula:

In another embodiment, the compound has formula:

In another embodiment, the compound has formula:

In another embodiment, the compound has formula:

In another embodiment, the compound has formula:

In another embodiment, the compound has formula:

In another embodiment, the compound has formula:

In another embodiment, the compound has formula:

In another embodiment, the compounds for use in the compositions andmethods provided herein have formula VI

-   -   or a pharmaceutically acceptable salt, solvate, hydrate,        stereoisomer or tautomer thereof, wherein

Y is NH, O or S; and

-   -   R^(6a) is (a) hydrogen; (b) (C₁-C₆)alkyl; (c)        (C₂-C₆)alkenyl; (d) (C₂-C₆)alkynyl; (e) (C₃-C₇)cycloalkyl; (f)        (C₁-C₆)alkyl substituted by aryl or heteroaryl; (g)        (C₂-C₄)alkenyl substituted by aryl or heteroaryl; (h)        (C₁-C₆)alkyl substituted by mono-, di-, or tri-halogen; (i)        (C₁-C₆)alkoxy substituted by mono-, di-, or tri-halogen; (j)        (C₁-C₆)alkylthio substituted by mono-, di-, or tri-halogen; (k)        aryl; or (l) heteroaryl, wherein said aryl and heteroaryl are        optionally substituted at a substitutable position with one or        more substituents selected from the group consisting of (a)        halogen; (b) cyano; (c) nitro; (d) hydroxy; (e) guanidino; (f)        heterocyclyl; (g) phenyl; (h) phenyloxy; (i) benzyl; (j)        benzyloxy; (k) —NR¹⁴R¹⁵; (l) —C(O)R⁹; (m)        —C(O)NR^(8a)R^(8b); (n) —OC(O)NR^(8a)R^(8b); (m) —NR⁷C(O)R⁹; (n)        —C(O)OR⁹; (o) —NR⁷C(O)OR⁹; (p) sulfamoyl; (q)        (C₁-C₆)alkylsulfonyl; (r) (C₁-C₆)alkylaminosulfonyl; (s)        di(C₁-C₆)alkylaminosulfonyl; (t) (C₁-C₆)alkyl optionally        substituted by mono-, di-, or tri-halogen; (u) (C₁-C₆)alkoxy        optionally substituted by mono-, di-, or tri-halogen; and (v)        (C₁-C₆)alkylthio optionally substituted by mono-, di-, or        tri-halogen.

The compounds provided herein may exist in a continuum of solid statesranging from fully amorphous to fully crystalline. The term ‘amorphous’refers to a state in which the material lacks long range order at themolecular level and, depending upon temperature, may exhibit thephysical properties of a solid or a liquid. Typically such materials donot give distinctive X-ray diffraction patterns and, while exhibitingthe properties of a solid, are more formally described as a liquid. Uponheating, a change from solid to liquid properties occurs which ischaracterized by a change of state, typically second order (‘glasstransition’). The term ‘crystalline’ refers to a solid phase in whichthe material has a regular ordered internal structure at the molecularlevel and gives a distinctive X-ray diffraction pattern with definedpeaks. Such materials, when heated sufficiently, will also exhibit theproperties of a liquid, but the change from solid to liquid ischaracterized by a phase change, typically first order (‘meltingpoint’).

The compounds provided herein may also exist in unsolvated and solvatedforms. A solvate form provided herein, for example, include hydrates. Acurrently accepted classification system for organic hydrates is onethat defines isolated site, channel, or metal-ion coordinatedhydrates—see Polymorphism in Pharmaceutical Solids by K. R. Morris (Ed.H. G. Brittain, CRC, 1999). Isolated site hydrates are ones in which thewater molecules are isolated from direct contact with each other byintervening organic molecules. In channel hydrates, the water moleculeslie in lattice channels where they are next to other water molecules. Inmetal-ion coordinated hydrates, the water molecules are bonded to themetal ion.

When the solvent or water is tightly bound, the complex will have awell-defined stoichiometry independent of humidity. When, however, thesolvent or water is weakly bound, as in channel solvates and hygroscopiccompounds, the water/solvent content will be dependent on humidity anddrying conditions. In such cases, non-stoichiometry will be the norm.

Also included within the scope of this disclosure are metabolites of thecompounds provided herein, that is, compounds formed in vivo uponadministration of a compound provided herein. Some examples ofmetabolites provided herein include

(i) where the compound contains a methyl group, an hydroxymethylderivative thereof (—CH₃->—CH₂OH):

(ii) where the compound contains an alkoxy group, an hydroxy derivativethereof (—OR->—OH);

(iii) where the compound contains a tertiary amino group, a secondaryamino derivative thereof (—NR¹R²->—NHR¹ or —NHR²);

(iv) where the compound contains a secondary amino group, a primaryderivative thereof (—NHR¹->—NH₂);

(v) where the contains a phenyl moiety, a phenol derivative thereof(—Ph->—PhOH); and

(vi) where the compound contains an amide group, a carboxylic acidderivative thereof (—CONH₂->COOH).

The compounds provided herein may also contain one or more asymmetriccarbon atoms and can exist as two or more stereoisomers. Where acompound provided herein contains an alkenyl or alkenylene group,geometric cis/trans (or Z/E) isomers are possible. Where structuralisomers are interconvertible via a low energy barrier, tautomericisomerism (‘tautomerism’) can occur. This can take the form of protontautomerism in compounds containing, for example, an imino, keto, oroxime group, or so-called valence tautomerism in compounds which containan aromatic moiety. It follows that a single compound may exhibit morethan one type of isomerism.

Included within the scope of the present disclosure are allstereoisomers, geometric isomers and tautomeric forms of the compoundsprovided herein, including compounds exhibiting more than one type ofisomerism, and mixtures of one or more thereof. Also included are acidor base salts wherein the counterion is optically active, for example,d-lactate or l-lysine, or racemic, for example, dl-tartrate ordl-arginine.

Cis/trans isomers may be separated by conventional techniques well knownto those skilled in the art, for example, chromatography and fractionalcrystallization.

Conventional techniques for the preparation/isolation of individualenantiomers include chiral synthesis from a suitable optically pureprecursor or resolution of the racemate (or the racemate of a salt orderivative) using, for example, chiral high pressure liquidchromatography (HPLC).

Alternatively, the racemate (or a racemic precursor) may be reacted witha suitable optically active compound, for example, an alcohol, or, inthe case where the compound of formula I contains an acidic or basicmoiety, a base or acid such as 1-phenylethylamine or tartaric acid. Theresulting diastereomeric mixture may be separated by chromatographyand/or fractional crystallization and one or both of thediastereoisomers converted to the corresponding pure enantiomer(s) bymeans well known to a skilled person.

Chiral compounds provided herein (and chiral precursors thereof) may beobtained in enantiomerically-enriched form using chromatography,typically HPLC, on an asymmetric resin with a mobile phase consisting ofa hydrocarbon, including heptane or hexane, containing from 0 to 50% byvolume of isopropanol, in one embodiment, from 2% to 20% in anotherembodiment, and from 0 to 5% by volume of an alkylamine, in oneembodiment 0.1% diethylamine. Concentration of the eluate affords theenriched mixture.

When any racemate crystallises, crystals of two different types arepossible. The first type is the racemic compound (true racemate)referred to above wherein one homogeneous form of crystal is producedcontaining both enantiomers in equimolar amounts. The second type is theracemic mixture or conglomerate wherein two forms of crystal areproduced in equimolar amounts each comprising a single enantiomer.

While both of the crystal forms present in a racemic mixture haveidentical physical properties, they may have different physicalproperties compared to the true racemate. Racemic mixtures may beseparated by conventional techniques known to those skilled in theart—see, for example, Stereochemistry of Organic Compounds by E. L.Eliel and S. H. Wilen (Wiley, 1994).

Also provided herein are isotopically enriched 2-S-benzyl pyrimidinecompounds.

Isotopic enrichment (for example, deuteration) of pharmaceuticals toimprove pharmacokinetics (“PK”), pharmacodynamics (“PD”), and toxicityprofiles, has been demonstrated previously with some classes of drugs.See, for example, Lijinsky et. al., Food Cosmet. Toxicol., 20: 393(1982); Lijinsky et. Nat. Cancer Inst., 69: 1127 (1982); Mangold et.al., Mutation Res. 308: 33 (1994); Gordon et. al., Drug Metab. Dispos.,15: 589 (1987); Zello et. al., Metabolism, 43: 487 (1994); Gately et.al., J. Nucl. Med., 27: 388 (1986); Wade D, Chem. Biol. Interact. 117:191 (1999).

Isotopic enrichment of a drug can be used, for example, to (1) reduce oreliminate unwanted metabolites, (2) increase the half-life of the parentdrug, (3) decrease the number of doses needed to achieve a desiredeffect, (4) decrease the amount of a dose necessary to achieve a desiredeffect, (5) increase the formation of active metabolites, if any areformed, and/or (6) decrease the production of deleterious metabolites inspecific tissues and/or create a more effective drug and/or a safer drugfor combination therapy, whether the combination therapy is intentionalor not.

Replacement of an atom for one of its isotopes often will result in achange in the reaction rate of a chemical reaction. This phenomenon isknown as the Kinetic Isotope Effect (“KIE”). For example, if a C—H bondis broken during a rate-determining step in a chemical reaction (i.e.the step with the highest transition state energy), substitution of adeuterium for that hydrogen will cause a decrease in the reaction rateand the process will slow down. This phenomenon is known as theDeuterium Kinetic Isotope Effect (“DKIE”). (See, e.g, Foster et al.,Adv. Drug Res., vol. 14, pp. 1-36 (1985); Kushner et al., Can. J.Physiol. Pharmacol., vol. 77, pp. 79-88 (1999)).

The magnitude of the DKIE can be expressed as the ratio between therates of a given reaction in which a C—H bond is broken, and the samereaction where deuterium is substituted for hydrogen. The DKIE can rangefrom about 1 (no isotope effect) to very large numbers, such as 50 ormore, meaning that the reaction can be fifty, or more, times slower whendeuterium is substituted for hydrogen. High DKIE values may be due inpart to a phenomenon known as tunneling, which is a consequence of theuncertainty principle. Tunneling is ascribed to the small mass of ahydrogen atom, and occurs because transition states involving a protoncan sometimes form in the absence of the required activation energy.Because deuterium has more mass than hydrogen, it statistically has amuch lower probability of undergoing this phenomenon.

Tritium (“T”) is a radioactive isotope of hydrogen, used in research,fusion reactors, neutron generators and radiopharmaceuticals. Tritium isa hydrogen atom that has 2 neutrons in the nucleus and has an atomicweight close to 3. It occurs naturally in the environment in very lowconcentrations, most commonly found as T₂O. Tritium decays slowly(half-life=12.3 years) and emits a low energy beta particle that cannotpenetrate the outer layer of human skin. Internal exposure is the mainhazard associated with this isotope, yet it must be ingested in largeamounts to pose a significant health risk. As compared with deuterium, alesser amount of tritium must be consumed before it reaches a hazardouslevel. Substitution of tritium (“T”) for hydrogen results in yet astronger bond than deuterium and gives numerically larger isotopeeffects. Similarly, substitution of isotopes for other elements,including, but not limited to, ¹³C or ¹⁴C for carbon, ³³S, ³⁴S, or ³⁶Sfor sulfur, ¹⁵N for nitrogen, and ¹⁷O or ¹⁸O for oxygen, may lead to asimilar kinetic isotope effect.

For example, the DKIE was used to decrease the hepatotoxicity ofhalothane by presumably limiting the production of reactive species suchas trifluoroacetyl chloride. However, this method may not be applicableto all drug classes. For example, deuterium incorporation can lead tometabolic switching. The concept of metabolic switching asserts thatxenogens, when sequestered by Phase I enzymes, may bind transiently andre-bind in a variety of conformations prior to the chemical reaction(e.g., oxidation). This hypothesis is supported by the relatively vastsize of binding pockets in many Phase I enzymes and the promiscuousnature of many metabolic reactions. Metabolic switching can potentiallylead to different proportions of known metabolites as well as altogethernew metabolites. This new metabolic profile may impart more or lesstoxicity.

The animal body expresses a variety of enzymes for the purpose ofeliminating foreign substances, such as therapeutic agents, from itscirculation system. Examples of such enzymes include the cytochrome P450enzymes (“CYPs”), esterases, proteases, reductases, dehydrogenases, andmonoamine oxidases, to react with and convert these foreign substancesto more polar intermediates or metabolites for renal excretion. Some ofthe most common metabolic reactions of pharmaceutical compounds involvethe oxidation of a carbon-hydrogen (C—H) bond to either a carbon-oxygen(C—O) or carbon-carbon (C—C) pi-bond. The resultant metabolites may bestable or unstable under physiological conditions, and can havesubstantially different pharmacokinetic, pharmacodynamic, and acute andlong-term toxicity profiles relative to the parent compounds. For manydrugs, such oxidations are rapid. These drugs therefore often requirethe administration of multiple or high daily doses.

Therefore, isotopic enrichment at certain positions of a compoundprovided herein will produce a detectable KIE that will affect thepharmacokinetic, pharmacologic, and/or toxicological profiles of acompound provided herein in comparison with a similar compound having anatural isotopic composition.

Preparation of the Compounds

The compounds provided herein are commercially available or can beprepared by routine chemical reactions known to one of skill in the art.General schemes for the preparation of exemplary compounds areillustrated below:

Isotopically enriched analogs of the compounds provided herein maygenerally be prepared according to the procedures shown above, whereinone or more of the reagents used is replaced by an isotopically enrichedreagent. Isotopically enriched reagents are commercially available ormay be prepared by routine chemical reactions known to one of skill inthe art. General schemes for the preparation of exemplary isotopicallyenriched compounds are illustrated below.

Triethyl 2,2-dideuteroethane-1,1,2-tricarboxylate, the deuteratedreagent of scheme 9 above, may be prepared, for example, fromcommercially bromoacetic acid-d3 as shown below.

Dimethylamine-d6, the deuterated reagent of scheme 10 above, iscommercially available. Other deuterated amines may be purchased orprepared by routine chemical reactions known to one of skill in the art.

Triethyl ethane-1,1,2-tricarboxylate-2-¹³C, the carbon-13 enrichedreagent of scheme 11 above, may be prepared from commerciallybromoacetic acid-2-¹³C as shown below. Bromoacetic acid-1-¹³C andbromoacetic acid-¹³C₂ are also commercially available, from whichadditional carbon-13 analogs may be prepared by routine chemicalreactions known to one of skill in the art.

Pharmaceutical Compositions

Also provided herein is a pharmaceutical composition which comprises acompound provided herein, or a pharmaceutically acceptable salt,solvate, hydrate, stereoisomer or tautomer thereof, as an activepharmaceutical ingredient, in combination with one or morepharmaceutically acceptable carriers or excipients. The choice ofexcipient, to a large extent, depends on factors, such as the particularmode of administration, the effect of the excipient on the solubilityand stability of the active ingredient, and the nature of the dosageform.

The pharmaceutical compositions provided herein may be provided inunit-dosage forms or multiple-dosage forms. Unit-dosage forms, as usedherein, refer to physically discrete units suitable for administrationto human and animal subjects and packaged individually as is known inthe art. Each unit-dose contains a predetermined quantity of the activeingredient(s) sufficient to produce the desired therapeutic effect, inassociation with the required pharmaceutical carriers or excipients.Examples of unit-dosage forms include ampoules, syringes, andindividually packaged tablets and capsules. Unit-dosage forms may beadministered in fractions or multiples thereof. A multiple-dosage formis a plurality of identical unit-dosage forms packaged in a singlecontainer to be administered in segregated unit-dosage form. Examples ofmultiple-dosage forms include vials, bottles of tablets or capsules, orbottles of pints or gallons.

The compounds provided herein may be administered alone, or incombination with one or more other compounds provided herein, one ormore other active ingredients. The pharmaceutical compositions thatcomprise a compound provided herein may be formulated in various dosageforms for oral, parenteral, and topical administration. Thepharmaceutical compositions may also be formulated as a modified releasedosage form, including delayed-, extended-, prolonged-, sustained-,pulsatile-, controlled-, accelerated- and fast-, targeted-,programmed-release, and gastric retention dosage forms. These dosageforms can be prepared according to conventional methods and techniquesknown to those skilled in the art (see, Remington: The Science andPractice of Pharmacy, supra; Modified-Release Drug Deliver Technology,Rathbone et al., Eds., Drugs and the Pharmaceutical Science, MarcelDekker, Inc.: New York, N.Y., 2002; Vol. 126).

The pharmaceutical compositions provided herein may be administered atonce, or multiple times at intervals of time. It is understood that theprecise dosage and duration of treatment may vary with the age, weight,and condition of the patient being treated, and may be determinedempirically using known testing protocols or by extrapolation from invivo or in vitro test or diagnostic data. It is further understood thatfor any particular individual, specific dosage regimens should beadjusted over time according to the individual need and the professionaljudgment of the person administering or supervising the administrationof the formulations.

A. Oral Administration

The pharmaceutical compositions provided herein may be provided insolid, semisolid, or liquid dosage forms for oral administration. Asused herein, oral administration also includes buccal, lingual, andsublingual administration. Suitable oral dosage forms include, but arenot limited to, tablets, capsules, pills, troches, lozenges, pastilles,cachets, pellets, medicated chewing gum, granules, bulk powders,effervescent or non-effervescent powders or granules, solutions,emulsions, suspensions, solutions, wafers, sprinkles, elixirs, andsyrups. In addition to the active ingredient(s), the pharmaceuticalcompositions may contain one or more pharmaceutically acceptablecarriers or excipients, including, but not limited to, binders, fillers,diluents, disintegrants, wetting agents, lubricants, glidants, coloringagents, dye-migration inhibitors, sweetening agents, and flavoringagents.

Binders or granulators impart cohesiveness to a tablet to ensure thetablet remaining intact after compression. Suitable binders orgranulators include, but are not limited to, starches, such as cornstarch, potato starch, and pre-gelatinized starch (e.g., STARCH 1500);gelatin; sugars, such as sucrose, glucose, dextrose, molasses, andlactose; natural and synthetic gums, such as acacia, alginic acid,alginates, extract of Irish moss, Panwar gum, ghatti gum, mucilage ofisabgol husks, carboxymethylcellulose, methylcellulose,polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, powderedtragacanth, and guar gum; celluloses, such as ethyl cellulose, celluloseacetate, carboxymethyl cellulose calcium, sodium carboxymethylcellulose, methyl cellulose, hydroxyethylcellulose (HEC),hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC);microcrystalline celluloses, such as AVICEL-PH-101, AVICEL-PH-103,AVICEL RC-581, AVICEL-PH-105 (FMC Corp., Marcus Hook, Pa.); and mixturesthereof. Suitable fillers include, but are not limited to, talc, calciumcarbonate, microcrystalline cellulose, powdered cellulose, dextrates,kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinizedstarch, and mixtures thereof. The binder or filler may be present fromabout 50 to about 99% by weight in the pharmaceutical compositionsprovided herein.

Suitable diluents include, but are not limited to, dicalcium phosphate,calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose,kaolin, mannitol, sodium chloride, dry starch, and powdered sugar.Certain diluents, such as mannitol, lactose, sorbitol, sucrose, andinositol, when present in sufficient quantity, can impart properties tosome compressed tablets that permit disintegration in the mouth bychewing. Such compressed tablets can be used as chewable tablets.

Suitable disintegrants include, but are not limited to, agar; bentonite;celluloses, such as methylcellulose and carboxymethylcellulose; woodproducts; natural sponge; cation-exchange resins; alginic acid; gums,such as guar gum and Veegum HV; citrus pulp; cross-linked celluloses,such as croscarmellose; cross-linked polymers, such as crospovidone;cross-linked starches; calcium carbonate; microcrystalline cellulose,such as sodium starch glycolate; polacrilin potassium; starches, such ascorn starch, potato starch, tapioca starch, and pre-gelatinized starch;clays; aligns; and mixtures thereof. The amount of disintegrant in thepharmaceutical compositions provided herein varies upon the type offormulation, and is readily discernible to those of ordinary skill inthe art. The pharmaceutical compositions provided herein may containfrom about 0.5 to about 15% or from about 1 to about 5% by weight of adisintegrant.

Suitable lubricants include, but are not limited to, calcium stearate;magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol;mannitol; glycols, such as glycerol behenate and polyethylene glycol(PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetableoil, including peanut oil, cottonseed oil, sunflower oil, sesame oil,olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyllaureate; agar; starch; lycopodium; silica or silica gels, such asAEROSIL® 200 (W.R. Grace Co., Baltimore, Md.) and CAB-O-SIL® (Cabot Co.of Boston, Mass.); and mixtures thereof. The pharmaceutical compositionsprovided herein may contain about 0.1 to about 5% by weight of alubricant.

Suitable glidants include colloidal silicon dioxide, CAB-O-SIL® (CabotCo. of Boston, Mass.), and asbestos-free talc. Coloring agents includeany of the approved, certified, water soluble FD&C dyes, and waterinsoluble FD&C dyes suspended on alumina hydrate, and color lakes andmixtures thereof. A color lake is the combination by adsorption of awater-soluble dye to a hydrous oxide of a heavy metal, resulting in aninsoluble form of the dye. Flavoring agents include natural flavorsextracted from plants, such as fruits, and synthetic blends of compoundswhich produce a pleasant taste sensation, such as peppermint and methylsalicylate. Sweetening agents include sucrose, lactose, mannitol,syrups, glycerin, and artificial sweeteners, such as saccharin andaspartame. Suitable emulsifying agents include gelatin, acacia,tragacanth, bentonite, and surfactants, such as polyoxyethylene sorbitanmonooleate (TWEEN® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN®80), and triethanolamine oleate. Suspending and dispersing agentsinclude sodium carboxymethylcellulose, pectin, tragacanth, Veegum,acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose, andpolyvinylpyrolidone. Preservatives include glycerin, methyl andpropylparaben, benzoic add, sodium benzoate and alcohol. Wetting agentsinclude propylene glycol monostearate, sorbitan monooleate, diethyleneglycol monolaurate, and polyoxyethylene lauryl ether. Solvents includeglycerin, sorbitol, ethyl alcohol, and syrup. Examples of non-aqueousliquids utilized in emulsions include mineral oil and cottonseed oil.Organic acids include citric and tartaric acid. Sources of carbondioxide include sodium bicarbonate and sodium carbonate.

It should be understood that many carriers and excipients may serveseveral functions, even within the same formulation.

The pharmaceutical compositions provided herein may be provided ascompressed tablets, tablet triturates, chewable lozenges, rapidlydissolving tablets, multiple compressed tablets, or enteric-coatingtablets, sugar-coated, or film-coated tablets. Enteric-coated tabletsare compressed tablets coated with substances that resist the action ofstomach acid but dissolve or disintegrate in the intestine, thusprotecting the active ingredients from the acidic environment of thestomach. Enteric-coatings include, but are not limited to, fatty acids,fats, phenylsalicylate, waxes, shellac, ammoniated shellac, andcellulose acetate phthalates. Sugar-coated tablets are compressedtablets surrounded by a sugar coating, which may be beneficial incovering up objectionable tastes or odors and in protecting the tabletsfrom oxidation. Film-coated tablets are compressed tablets that arecovered with a thin layer or film of a water-soluble material. Filmcoatings include, but are not limited to, hydroxyethylcellulose, sodiumcarboxymethylcellulose, polyethylene glycol 4000, and cellulose acetatephthalate. Film coating imparts the same general characteristics assugar coating. Multiple compressed tablets are compressed tablets madeby more than one compression cycle, including layered tablets, andpress-coated or dry-coated tablets.

The tablet dosage forms may be prepared from the active ingredient inpowdered, crystalline, or granular forms, alone or in combination withone or more carriers or excipients described herein, including binders,disintegrants, controlled-release polymers, lubricants, diluents, and/orcolorants. Flavoring and sweetening agents are especially useful in theformation of chewable tablets and lozenges.

The pharmaceutical compositions provided herein may be provided as softor hard capsules, which can be made from gelatin, methylcellulose,starch, or calcium alginate. The hard gelatin capsule, also known as thedry-filled capsule (DFC), consists of two sections, one slipping overthe other, thus completely enclosing the active ingredient. The softelastic capsule (SEC) is a soft, globular shell, such as a gelatinshell, which is plasticized by the addition of glycerin, sorbitol, or asimilar polyol. The soft gelatin shells may contain a preservative toprevent the growth of microorganisms. Suitable preservatives are thoseas described herein, including methyl- and propyl-parabens, and sorbicacid. The liquid, semisolid, and solid dosage forms provided herein maybe encapsulated in a capsule. Suitable liquid and semisolid dosage formsinclude solutions and suspensions in propylene carbonate, vegetableoils, or triglycerides. Capsules containing such solutions can beprepared as described in U.S. Pat. Nos. 4,328,245; 4,409,239; and4,410,545. The capsules may also be coated as known by those of skill inthe art in order to modify or sustain dissolution of the activeingredient.

The pharmaceutical compositions provided herein may be provided inliquid and semisolid dosage forms, including emulsions, solutions,suspensions, elixirs, and syrups. An emulsion is a two-phase system, inwhich one liquid is dispersed in the form of small globules throughoutanother liquid, which can be oil-in-water or water-in-oil. Emulsions mayinclude a pharmaceutically acceptable non-aqueous liquids or solvent,emulsifying agent, and preservative. Suspensions may include apharmaceutically acceptable suspending agent and preservative. Aqueousalcoholic solutions may include a pharmaceutically acceptable acetal,such as a di(lower alkyl)acetal of a lower alkyl aldehyde, e.g.,acetaldehyde diethyl acetal; and a water-miscible solvent having one ormore hydroxyl groups, such as propylene glycol and ethanol. Elixirs areclear, sweetened, and hydroalcoholic solutions. Syrups are concentratedaqueous solutions of a sugar, for example, sucrose, and may also containa preservative. For a liquid dosage form, for example, a solution in apolyethylene glycol may be diluted with a sufficient quantity of apharmaceutically acceptable liquid carrier, e.g., water, to be measuredconveniently for administration.

Other useful liquid and semisolid dosage forms include, but are notlimited to, those containing the active ingredient(s) provided herein,and a dialkylated mono- or poly-alkylene glycol, including,1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethyleneglycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether,polyethyleneglycol-750-dimethyl ether, wherein 350, 550, and 750 referto the approximate average molecular weight of the polyethylene glycol.These formulations may further comprise one or more antioxidants, suchas butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA),propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine,lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoricacid, bisulfite, sodium metabisulfite, thiodipropionic acid and itsesters, and dithiocarbamates.

The pharmaceutical compositions provided herein for oral administrationmay be also provided in the forms of liposomes, micelles, microspheres,or nanosystems. Miccellar dosage forms can be prepared as described inU.S. Pat. No. 6,350,458.

The pharmaceutical compositions provided herein may be provided asnon-effervescent or effervescent, granules and powders, to bereconstituted into a liquid dosage form. Pharmaceutically acceptablecarriers and excipients used in the non-effervescent granules or powdersmay include diluents, sweeteners, and wetting agents. Pharmaceuticallyacceptable carriers and excipients used in the effervescent granules orpowders may include organic acids and a source of carbon dioxide.

Coloring and flavoring agents can be used in all of the above dosageforms.

The pharmaceutical compositions provided herein may be formulated asimmediate or modified release dosage forms, including delayed-,sustained, pulsed-, controlled, targeted-, and programmed-release forms.

The pharmaceutical compositions provided herein may be co-formulatedwith other active ingredients which do not impair the desiredtherapeutic action, or with substances that supplement the desiredaction, such as antacids, proton pump inhibitors, and H₂-receptorantagonists.

B. Parenteral Administration

The pharmaceutical compositions provided herein may be administeredparenterally by injection, infusion, or implantation, for local orsystemic administration. Parenteral administration, as used herein,include intravenous, intraarterial, intraperitoneal, intrathecal,intraventricular, intraurethral; intrasternal, intracranial,intramuscular, intrasynovial, and subcutaneous administration.

The pharmaceutical compositions provided herein may be formulated in anydosage forms that are suitable for parenteral administration, includingsolutions, suspensions, emulsions, micelles, liposomes, microspheres,nanosystems, and solid forms suitable for solutions or suspensions inliquid prior to injection. Such dosage forms can be prepared accordingto conventional methods known to those skilled in the art ofpharmaceutical science (see, Remington. The Science and Practice ofPharmacy, supra).

The pharmaceutical compositions intended for parenteral administrationmay include one or more pharmaceutically acceptable carriers andexcipients, including, but not limited to, aqueous vehicles,water-miscible vehicles, non-aqueous vehicles, antimicrobial agents orpreservatives against the growth of microorganisms, stabilizers,solubility enhancers, isotonic agents, buffering agents, antioxidants,local anesthetics, suspending and dispersing agents, wetting oremulsifying agents, complexing agents, sequestering or chelating agents,cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents,and inert gases.

Suitable aqueous vehicles include, but are not limited to, water,saline, physiological saline or phosphate buffered saline (PBS), sodiumchloride injection, Ringers injection, isotonic dextrose injection,sterile water injection, dextrose and lactated Ringers injection.Non-aqueous vehicles include, but are not limited to, fixed oils ofvegetable origin, castor oil, corn oil, cottonseed oil, olive oil,peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil,hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chaintriglycerides of coconut oil, and palm seed oil. Water-miscible vehiclesinclude, but are not limited to, ethanol, 1,3-butanediol, liquidpolyethylene glycol (e.g., polyethylene glycol 300 and polyethyleneglycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone,dimethylacetamide, and dimethylsulfoxide.

Suitable antimicrobial agents or preservatives include, but are notlimited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol,methyl and propyl p-hydroxybenzates, thimerosal, benzalkonium chloride,benzethonium chloride, methyl- and propyl-parabens, and sorbic acid.Suitable isotonic agents include, but are not limited to, sodiumchloride, glycerin, and dextrose. Suitable buffering agents include, butare not limited to, phosphate and citrate. Suitable antioxidants arethose as described herein, including bisulfite and sodium metabisulfite.Suitable local anesthetics include, but are not limited to, procainehydrochloride. Suitable suspending and dispersing agents are those asdescribed herein, including sodium carboxymethylcelluose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agentsinclude those described herein, including polyoxyethylene sorbitanmonolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamineoleate. Suitable sequestering or chelating agents include, but are notlimited to EDTA. Suitable pH adjusting agents include, but are notlimited to, sodium hydroxide, hydrochloric acid, citric acid, and lacticacid. Suitable complexing agents include, but are not limited to,cyclodextrins, including alpha-cyclodextrin, beta-cyclodextrin,hydroxypropyl-beta-cyclodextrin, sulfobutylether-beta-cyclodextrin, andsulfobutylether 7-beta-cyclodextrin (CAPTISOL®, CyDex, Lenexa, Kans.).

The pharmaceutical compositions provided herein may be formulated forsingle or multiple dosage administration. The single dosage formulationsare packaged in an ampule, a vial, or a syringe. The multiple dosageparenteral formulations must contain an antimicrobial agent atbacteriostatic or fungistatic concentrations. All parenteralformulations must be sterile, as known and practiced in the art.

In one embodiment, the pharmaceutical compositions are provided asready-to-use sterile solutions. In another embodiment, thepharmaceutical compositions are provided as sterile dry solubleproducts, including lyophilized powders and hypodermic tablets, to bereconstituted with a vehicle prior to use. In yet another embodiment,the pharmaceutical compositions are provided as ready-to-use sterilesuspensions. In yet another embodiment, the pharmaceutical compositionsare provided as sterile dry insoluble products to be reconstituted witha vehicle prior to use. In still another embodiment, the pharmaceuticalcompositions are provided as ready-to-use sterile emulsions.

The pharmaceutical compositions provided herein may be formulated asimmediate or modified release dosage forms, including delayed-,sustained, pulsed-, controlled, targeted-, and programmed-release forms.

The pharmaceutical compositions may be formulated as a suspension,solid, semi-solid, or thixotropic liquid, for administration as animplanted depot. In one embodiment, the pharmaceutical compositionsprovided herein are dispersed in a solid inner matrix, which issurrounded by an outer polymeric membrane that is insoluble in bodyfluids but allows the active ingredient in the pharmaceuticalcompositions diffuse through.

Suitable inner matrixes include polymethylmethacrylate,polybutylmethacrylate, plasticized or unplasticized polyvinylchloride,plasticized nylon, plasticized polyethyleneterephthalate, naturalrubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene,ethylene-vinylacetate copolymers, silicone rubbers,polydimethylsiloxanes, silicone carbonate copolymers, hydrophilicpolymers, such as hydrogels of esters of acrylic and methacrylic acid,collagen, cross-linked polyvinylalcohol, and cross-linked partiallyhydrolyzed polyvinyl acetate.

Suitable outer polymeric membranes include polyethylene, polypropylene,ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers,ethylene/vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride,vinylchloride copolymers with vinyl acetate, vinylidene chloride,ethylene and propylene, ionomer polyethylene terephthalate, butyl rubberepichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer, andethylene/vinyloxyethanol copolymer.

C. Topical Administration

The pharmaceutical compositions provided herein may be administeredtopically to the skin, orifices, or mucosa. The topical administration,as used herein, include (intra)dermal, conjuctival, intracorneal,intraocular, ophthalmic, auricular, transdermal, nasal, vaginal,uretheral, respiratory, and rectal administration.

The pharmaceutical compositions provided herein may be formulated in anydosage forms that are suitable for topical administration for local orsystemic effect, including emulsions, solutions, suspensions, creams,gels, hydrogels, ointments, dusting powders, dressings, elixirs,lotions, suspensions, tinctures, pastes, foams, films, aerosols,irrigations, sprays, suppositories, bandages, dermal patches. Thetopical formulation of the pharmaceutical compositions provided hereinmay also comprise liposomes, micelles, microspheres, nanosystems, andmixtures thereof.

Pharmaceutically acceptable carriers and excipients suitable for use inthe topical formulations provided herein include, but are not limitedto, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles,antimicrobial agents or preservatives against the growth ofmicroorganisms, stabilizers, solubility enhancers, isotonic agents,buffering agents, antioxidants, local anesthetics, suspending anddispersing agents, wetting or emulsifying agents, complexing agents,sequestering or chelating agents, penetration enhancers,cryopretectants, lyoprotectants, thickening agents, and inert gases.

The pharmaceutical compositions may also be administered topically byelectroporation, iontophoresis, phonophoresis, sonophoresis andmicroneedle or needle-free injection, such as POWDERJECT™ (Chiron Corp.,Emeryville, Calif.), and BIOJECT™ (Bioject Medical Technologies Inc.,Tualatin, Oreg.).

The pharmaceutical compositions provided herein may be provided in theforms of ointments, creams, and gels. Suitable ointment vehicles includeoleaginous or hydrocarbon bases, including lard, benzoinated lard, oliveoil, cottonseed oil, white petrolatum, and plastibase; emulsifiable orabsorption bases, such as hydrophilic petrolatum, hydroxystearinsulfate, and anhydrous lanolin; water-removable bases, such ashydrophilic ointment; water-soluble ointment bases, includingpolyethylene glycols of varying molecular weight; emulsion bases, eitherwater-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions, includingcetyl alcohol, glyceryl monostearate, lanolin, and stearic acid (see,Remington: The Science and Practice of Pharmacy, supra). These vehiclesare emollient but generally require addition of antioxidants andpreservatives.

Suitable cream base can be oil-in-water or water-in-oil. Cream vehiclesmay be water-washable, and contain an oil phase, an emulsifier, and anaqueous phase. The oil phase is also called the “internal” phase, whichis generally comprised of petrolatum and a fatty alcohol such as cetylor stearyl alcohol. The aqueous phase usually, although not necessarily,exceeds the oil phase in volume, and generally contains a humectant. Theemulsifier in a cream formulation may be a nonionic, anionic, cationic,or amphoteric surfactant.

Gels are semisolid, suspension-type systems. Single-phase gels containorganic macromolecules distributed substantially uniformly throughoutthe liquid carrier. Suitable gelling agents include crosslinked acrylicacid polymers, such as carbomers, carboxypolyalkylenes, Carbopol®;hydrophilic polymers, such as polyethylene oxides,polyoxyethylene-polyoxypropylene copolymers, and polyvinylalcohol;cellulosic polymers, such as hydroxypropyl cellulose, hydroxyethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulosephthalate, and methylcellulose; gums, such as tragacanth and xanthangum; sodium alginate; and gelatin. In order to prepare a uniform gel,dispersing agents such as alcohol or glycerin can be added, or thegelling agent can be dispersed by trituration, mechanical mixing, and/orstirring.

The pharmaceutical compositions provided herein may be administeredrectally, urethrally, vaginally, or perivaginally in the forms ofsuppositories, pessaries, bougies, poultices or cataplasm, pastes,powders, dressings, creams, plasters, contraceptives, ointments,solutions, emulsions, suspensions, tampons, gels, foams, sprays, orenemas. These dosage forms can be manufactured using conventionalprocesses as described in Remington: The Science and Practice ofPharmacy, supra.

Rectal, urethral, and vaginal suppositories are solid bodies forinsertion into body orifices, which are solid at ordinary temperaturesbut melt or soften at body temperature to release the activeingredient(s) inside the orifices. Pharmaceutically acceptable carriersutilized in rectal and vaginal suppositories include vehicles, such asstiffening agents, which produce a melting point in the proximity ofbody temperature, when formulated with the pharmaceutical compositionsprovided herein; and antioxidants as described herein, includingbisulfite and sodium metabisulfite. Suitable vehicles include, but arenot limited to, cocoa butter (theobroma oil), glycerin-gelatin, carbowax(polyoxyethylene glycol), spermaceti, paraffin, white and yellow wax,and appropriate mixtures of mono-, di- and triglycerides of fatty acids,hydrogels, such as polyvinyl alcohol, hydroxyethyl methacrylate,polyacrylic acid; glycerinated gelatin. Combinations of the variousvehicles may be used. Rectal and vaginal suppositories may be preparedby the compressed method or molding. The typical weight of a rectal andvaginal suppository is about 2 to 3 g.

The pharmaceutical compositions provided herein may be administeredophthalmically in the forms of solutions, suspensions, ointments,emulsions, gel-forming solutions, powders for solutions, gels, ocularinserts, and implants.

The pharmaceutical compositions provided herein may be administeredintranasally or by inhalation to the respiratory tract. Thepharmaceutical compositions may be provided in the form of an aerosol orsolution for delivery using a pressurized container, pump, spray,atomizer, such as an atomizer using electrohydrodynamics to produce afine mist, or nebulizer, alone or in combination with a suitablepropellant, such as 1,1,1,2-tetrafluoroethane or1,1,1,2,3,3,3-heptafluoropropane. The pharmaceutical compositions mayalso be provided as a dry powder for insufflation, alone or incombination with an inert carrier such as lactose or phospholipids; andnasal drops. For intranasal use, the powder may comprise a bioadhesiveagent, including chitosan or cyclodextrin.

Solutions or suspensions for use in a pressurized container, pump,spray, atomizer, or nebulizer may be formulated to contain ethanol,aqueous ethanol, or a suitable alternative agent for dispersing,solubilizing, or extending release of the active ingredient providedherein, a propellant as solvent; and/or a surfactant, such as sorbitantrioleate, oleic acid, or an oligolactic acid.

The pharmaceutical compositions provided herein may be micronized to asize suitable for delivery by inhalation, such as 50 micrometers orless, or 10 micrometers or less. Particles of such sizes may be preparedusing a comminuting method known to those skilled in the art, such asspiral jet milling, fluid bed jet milling, supercritical fluidprocessing to form nanoparticles, high pressure homogenization, or spraydrying.

Capsules, blisters and cartridges for use in an inhaler or insufflatormay be formulated to contain a powder mix of the pharmaceuticalcompositions provided herein; a suitable powder base, such as lactose orstarch; and a performance modifier, such as l-leucine, mannitol, ormagnesium stearate. The lactose may be anhydrous or in the form of themonohydrate. Other suitable excipients include dextran, glucose,maltose, sorbitol, xylitol, fructose, sucrose, and trehalose. Thepharmaceutical compositions provided herein for inhaled/intranasaladministration may further comprise a suitable flavor, such as mentholand levomenthol, or sweeteners, such as saccharin or saccharin sodium.

The pharmaceutical compositions provided herein for topicaladministration may be formulated to be immediate release or modifiedrelease, including delayed-, sustained-, pulsed-, controlled-, targeted,and programmed release.

D. Modified Release

The pharmaceutical compositions provided herein may be formulated as amodified release dosage form. As used herein, the term “modifiedrelease” refers to a dosage form in which the rate or place of releaseof the active ingredient(s) is different from that of an immediatedosage form when administered by the same route. Modified release dosageforms include delayed-, extended-, prolonged-, sustained-, pulsatile- orpulsed-, controlled-, accelerated- and fast-, targeted-,programmed-release, and gastric retention dosage forms. Thepharmaceutical compositions in modified release dosage forms can beprepared using a variety of modified release devices and methods knownto those skilled in the art, including, but not limited to, matrixcontrolled release devices, osmotic controlled release devices,multiparticulate controlled release devices, ion-exchange resins,enteric coatings, multilayered coatings, microspheres, liposomes, andcombinations thereof. The release rate of the active ingredient(s) canalso be modified by varying the particle sizes and polymorphorism of theactive ingredient(s).

Examples of modified release include, but are not limited to, thosedescribed in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123;4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543;5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474;5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324;6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461;6,419,961; 6,589,548; 6,613,358; and 6,699,500.

1. Matrix Controlled Release Devices

The pharmaceutical compositions provided herein in a modified releasedosage form may be fabricated using a matrix controlled release deviceknown to those skilled in the art (see, Takada et al. in “Encyclopediaof Controlled Drug Delivery,” Vol. 2, Mathiowitz ed., Wiley, 1999).

In one embodiment, the pharmaceutical compositions provided herein in amodified release dosage form is formulated using an erodible matrixdevice, which is water-swellable, erodible, or soluble polymers,including synthetic polymers, and naturally occurring polymers andderivatives, such as polysaccharides and proteins.

Materials useful in forming an erodible matrix include, but are notlimited to, chitin, chitosan, dextran, and pullulan; gum agar, gumarabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, gumghatti, guar gum, xanthan gum, and scleroglucan; starches, such asdextrin and maltodextrin; hydrophilic colloids, such as pectin;phosphatides, such as lecithin; alginates; propylene glycol alginate;gelatin; collagen; and cellulosics, such as ethyl cellulose (EC),methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC,hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), celluloseacetate (CA), cellulose propionate (CP), cellulose butyrate (CB),cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetatetrimellitate (HPMCAT), and ethylhydroxy ethylcellulose (EHEC); polyvinylpyrrolidone; polyvinyl alcohol; polyvinyl acetate; glycerol fatty acidesters; polyacrylamide; polyacrylic acid; copolymers of ethacrylic acidor methacrylic acid (EUDRAGIT®, Rohm America, Inc., Piscataway, N.J.);poly(2-hydroxyethyl-methacrylate); polylactides; copolymers ofL-glutamic acid and ethyl-L-glutamate; degradable lactic acid-glycolicacid copolymers; poly-D-(−)-3-hydroxybutyric acid; and other acrylicacid derivatives, such as homopolymers and copolymers ofbutylmethacrylate, methylmethacrylate, ethylmethacrylate, ethylacrylate,(2-dimethylaminoethyl)methacrylate, and(trimethylaminoethyl)methacrylate chloride.

In another embodiment, the pharmaceutical compositions are formulatedwith a non-erodible matrix device. The active ingredient(s) is dissolvedor dispersed in an inert matrix and is released primarily by diffusionthrough the inert matrix once administered. Materials suitable for useas a non-erodible matrix device included, but are not limited to,insoluble plastics, such as polyethylene, polypropylene, polyisoprene,polyisobutylene, polybutadiene, polymethylmethacrylate,polybutylmethacrylate, chlorinated polyethylene, polyvinylchloride,methyl acrylate-methyl methacrylate copolymers, ethylene-vinylacetatecopolymers, ethylene/propylene copolymers, ethylene/ethyl acrylatecopolymers, vinylchloride copolymers with vinyl acetate, vinylidenechloride, ethylene and propylene, ionomer polyethylene terephthalate,butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer, andethylene/vinyloxyethanol copolymer, polyvinyl chloride, plasticizednylon, plasticized polyethyleneterephthalate, natural rubber, siliconerubbers, polydimethylsiloxanes, silicone carbonate copolymers, and;hydrophilic polymers, such as ethyl cellulose, cellulose acetate,crospovidone, and cross-linked partially hydrolyzed polyvinyl acetate;and fatty compounds, such as carnauba wax, microcrystalline wax, andtriglycerides.

In a matrix controlled release system, the desired release kinetics canbe controlled, for example, via the polymer type employed, the polymerviscosity, the particle sizes of the polymer and/or the activeingredient(s), the ratio of the active ingredient(s) versus the polymer,and other excipients in the compositions.

The pharmaceutical compositions provided herein in a modified releasedosage form may be prepared by methods known to those skilled in theart, including direct compression, dry or wet granulation followed bycompression, melt-granulation followed by compression.

2. Osmotic Controlled Release Devices

The pharmaceutical compositions provided herein in a modified releasedosage form may be fabricated using an osmotic controlled releasedevice, including one-chamber system, two-chamber system, asymmetricmembrane technology (AMT), and extruding core system (ECS). In general,such devices have at least two components: (a) the core which containsthe active ingredient(s); and (b) a semipermeable membrane with at leastone delivery port, which encapsulates the core. The semipermeablemembrane controls the influx of water to the core from an aqueousenvironment of use so as to cause drug release by extrusion through thedelivery port(s).

In addition to the active ingredient(s), the core of the osmotic deviceoptionally includes an osmotic agent, which creates a driving force fortransport of water from the environment of use into the core of thedevice. One class of osmotic agents water-swellable hydrophilicpolymers, which are also referred to as “osmopolymers” and “hydrogels,”including, but not limited to, hydrophilic vinyl and acrylic polymers,polysaccharides such as calcium alginate, polyethylene oxide (PEO),polyethylene glycol (PEG), polypropylene glycol (PPG),poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic)acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol(PVA), PVA/PVP copolymers, PVA/PVP copolymers with hydrophobic monomerssuch as methyl methacrylate and vinyl acetate, hydrophilic polyurethanescontaining large PEO blocks, sodium croscarmellose, carrageenan,hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC),hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) andcarboxyethyl, cellulose (CEC), sodium alginate, polycarbophil, gelatin,xanthan gum, and sodium starch glycolate.

The other class of osmotic agents is osmogens, which are capable ofimbibing water to affect an osmotic pressure gradient across the barrierof the surrounding coating. Suitable osmogens include, but are notlimited to, inorganic salts, such as magnesium sulfate, magnesiumchloride, calcium chloride, sodium chloride, lithium chloride, potassiumsulfate, potassium phosphates, sodium carbonate, sodium sulfite, lithiumsulfate, potassium chloride, and sodium sulfate; sugars, such asdextrose, fructose, glucose, inositol, lactose, maltose, mannitol,raffinose, sorbitol, sucrose, trehalose, and xylitol; organic acids,such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleicacid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamicacid, p-toluenesulfonic acid, succinic acid, and tartaric acid; urea;and mixtures thereof.

Osmotic agents of different dissolution rates may be employed toinfluence how rapidly the active ingredient(s) is initially deliveredfrom the dosage form. For example, amorphous sugars, such as MannogemeEZ (SPI Pharma, Lewes, Del.) can be used to provide faster deliveryduring the first couple of hours to promptly produce the desiredtherapeutic effect, and gradually and continually release of theremaining amount to maintain the desired level of therapeutic orprophylactic effect over an extended period of time. In this case, theactive ingredient(s) is released at such a rate to replace the amount ofthe active ingredient metabolized and excreted.

The core may also include a wide variety of other excipients andcarriers as described herein to enhance the performance of the dosageform or to promote stability or processing.

Materials useful in forming the semipermeable membrane include variousgrades of acrylics, vinyls, ethers, polyamides, polyesters, andcellulosic derivatives that are water-permeable and water-insoluble atphysiologically relevant pHs, or are susceptible to being renderedwater-insoluble by chemical alteration, such as crosslinking. Examplesof suitable polymers useful in forming the coating, include plasticized,unplasticized, and reinforced cellulose acetate (CA), cellulosediacetate, cellulose triacetate, CA propionate, cellulose nitrate,cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methylcarbamate, CA succinate, cellulose acetate trimellitate (CAT), CAdimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyloxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluenesulfonate, agar acetate, amylose triacetate, beta glucan acetate, betaglucan triacetate, acetaldehyde dimethyl acetate, triacetate of locustbean gum, hydroxlated ethylene-vinylacetate, EC, PEG, PPG, PEG/PPGcopolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT,poly(acrylic) acids and esters and poly-(methacrylic) acids and estersand copolymers thereof, starch, dextran, dextrin, chitosan, collagen,gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones,polystyrenes, polyvinyl halides, polyvinyl esters and ethers, naturalwaxes, and synthetic waxes.

Semipermeable membrane may also be a hydrophobic microporous membrane,wherein the pores are substantially filled with a gas and are not wettedby the aqueous medium but are permeable to water vapor, as disclosed inU.S. Pat. No. 5,798,119. Such hydrophobic but water-vapor permeablemembrane are typically composed of hydrophobic polymers such aspolyalkenes, polyethylene, polypropylene, polytetrafluoroethylene,polyacrylic acid derivatives, polyethers, polysulfones,polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidenefluoride, polyvinyl esters and ethers, natural waxes, and syntheticwaxes.

The delivery port(s) on the semipermeable membrane may be formedpost-coating by mechanical or laser drilling. Delivery port(s) may alsobe formed in situ by erosion of a plug of water-soluble material or byrupture of a thinner portion of the membrane over an indentation in thecore. In addition, delivery ports may be formed during coating process,as in the case of asymmetric membrane coatings of the type disclosed inU.S. Pat. Nos. 5,612,059 and 5,698,220.

The total amount of the active ingredient(s) released and the releaserate can substantially by modulated via the thickness and porosity ofthe semipermeable membrane, the composition of the core, and the number,size, and position of the delivery ports.

The pharmaceutical compositions in an osmotic controlled-release dosageform may further comprise additional conventional excipients asdescribed herein to promote performance or processing of theformulation.

The osmotic controlled-release dosage forms can be prepared according toconventional methods and techniques known to those skilled in the art(see, Remington: The Science and Practice of Pharmacy, supra; Santus andBaker, J Controlled Release 1995, 35, 1-21; Verma et al., DrugDevelopment and Industrial Pharmacy 2000, 26, 695-708; Verma et al., J.Controlled Release 2002, 79, 7-27).

In certain embodiments, the pharmaceutical compositions provided hereinare formulated as AMT controlled-release dosage form, which comprises anasymmetric osmotic membrane that coats a core comprising the activeingredient(s) and other pharmaceutically acceptable excipients. See,U.S. Pat. No. 5,612,059 and WO 2002/17918. The AMT controlled-releasedosage forms can be prepared according to conventional methods andtechniques known to those skilled in the art, including directcompression, dry granulation, wet granulation, and a dip-coating method.

In certain embodiments, the pharmaceutical compositions provided hereinare formulated as ESC controlled-release dosage form, which comprises anosmotic membrane that coats a core comprising the active ingredient(s),hydroxylethyl cellulose, and other pharmaceutically acceptableexcipients.

3. Multiparticulate Controlled Release Devices

The pharmaceutical compositions provided herein in a modified releasedosage form may be fabricated a multiparticulate controlled releasedevice, which comprises a multiplicity of particles, granules, orpellets, ranging from about 10 μm to about 3 mm, about 50 μm to about2.5 mm, or from about 100 μm to 1 mm in diameter. Such multiparticulatesmay be made by the processes know to those skilled in the art, includingwet- and dry-granulation, extrusion/spheronization, roller-compaction,melt-congealing, and by spray-coating seed cores. See, for example,Multiparticulate Oral Drug Delivery; Marcel Dekker: 1994; andPharmaceutical Pelletization Technology; Marcel Dekker: 1989.

Other excipients as described herein may be blended with thepharmaceutical compositions to aid in processing and forming themultiparticulates. The resulting particles may themselves constitute themultiparticulate device or may be coated by various film-formingmaterials, such as enteric polymers, water-swellable, and water-solublepolymers. The multiparticulates can be further processed as a capsule ora tablet.

4. Targeted Delivery

The pharmaceutical compositions provided herein may also be formulatedto be targeted to a particular tissue, receptor, or other area of thebody of the subject to be treated, including liposome-, resealederythrocyte-, and antibody-based delivery systems. Examples include, butare not limited to, U.S. Pat. Nos. 6,316,652; 6,274,552; 6,271,359;6,253,872; 6,139,865; 6,131,570; 6,120,751; 6,071,495; 6,060,082;6,048,736; 6,039,975; 6,004,534; 5,985,307; 5,972,366; 5,900,252;5,840,674; 5,759,542; and 5,709,874.

Methods of Use

In one embodiment, provided is a method of treating, preventing, orameliorating one or more symptoms of a disorder or disease associatedwith CRTH2 and/or one or more other PGD₂ receptors by administering to asubject having or being suspected to have such a condition or disease, atherapeutically effective amount of a compound provided herein, or apharmaceutically acceptable salt, solvate, hydrate, stereoisomer ortautomer thereof; or a pharmaceutical composition thereof.

In another embodiments, provided herein is a method of treating,preventing, or ameliorating one or more symptoms of a disease ordisorder responsive to modulation of CRTH2 and/or one or more other PGD₂receptors, comprising administering to a subject having or beingsuspected to have such a disease or disorder, a therapeuticallyeffective amount of one or more of the compounds or compositionsprovided herein.

In yet another embodiment, provided herein is a method of treating,preventing, or ameliorating one or more symptoms of a disease ordisorder mediated by CRTH2 and/or one or more other PGD₂ receptors,comprising administering to a subject having or being suspected to havesuch a condition or disease, a therapeutically effective amount of oneor more of the compounds or compositions provided herein.

In yet another embodiment, provided herein is a method for treating,preventing, or ameliorating one or more symptoms of aneosinophil-related disease, comprising administering to a subject atherapeutically effective amount of a compound provided herein, or apharmaceutically acceptable salt, solvate, hydrate, stereoisomer ortautomer thereof; or a pharmaceutical composition thereof.

In yet another embodiment, provided herein is a method for treating,preventing, or ameliorating one or more symptoms of a basophil-relateddisease, comprising administering to a subject a therapeuticallyeffective amount of a compound provided herein, or a pharmaceuticallyacceptable salt, solvate, hydrate, stereoisomer or tautomer thereof; ora pharmaceutical composition thereof.

In still another embodiment, provided herein is a method for treating,preventing, or ameliorating one or more symptoms of an inflammatorydisease, comprising administering to a subject a therapeuticallyeffective amount of a compound provided herein, or a pharmaceuticallyacceptable salt, solvate, hydrate, stereoisomer or tautomer thereof; ora pharmaceutical composition thereof.

The disorders and diseases treatable with one or more of the compoundsprovided herein include, but are not limited to, (1) inflammatory orallergic diseases, including systemic anaphylaxis and hypersensitivitydisorders, atopic dermatitis, urticaria, drug allergies, insect stingallergies, food allergies (including celiac disease and the like), andmastocytosis; (2) inflammatory bowel diseases, including Crohn'sdisease, ulcerative colitis, ileitis, and enteritis; (3) vasculitis, andBehcet's syndrome; (4) psoriasis and inflammatory dermatoses, includingdermatitis, eczema, atopic dermatitis, allergic contact dermatitis,urticaria, viral cutaneous pathologies including those derived fromhuman papillomavirus, HIV or RLV infection, bacterial, flugal, and otherparasital cutaneous pathologies, and cutaneous lupus erythematosus; (5)asthma and respiratory allergic diseases, including allergic asthma,exercise induced asthma, allergic rhinitis, otitis media, allergicconjunctivitis, hypersensitivity lung diseases, and chronic obstructivepulmonary disease; (6) autoimmune diseases, including arthritis(including rheumatoid and psoriatic), systemic lupus erythematosus, typeI diabetes, myasthenia gravis, multiple sclerosis, Graves' disease, andglomerulonephritis; (7) graft rejection (including allograft rejectionand graft-v-host disease), e.g., skin graft rejection, solid organtransplant rejection, bone marrow transplant rejection; (8) fever; (9)cardiovascular disorders, including acute heart failure, hypotension,hypertension, angina pectoris, myocardial infarction, cardiomyopathy,congestive heart failure, atherosclerosis, coronary artery disease,restenosis, and vascular stenosis; (10) cerebrovascular disorders,including traumatic brain injury, stroke, ischemic reperfusion injuryand aneurysm; (11) cancers of the breast, skin, prostate, cervix,uterus, ovary, testes, bladder, lung, liver, larynx, oral cavity, colonand gastrointestinal tract (e.g., esophagus, stomach, pancreas), brain,thyroid, blood, and lymphatic system; (12) fibrosis, connective tissuedisease, and sarcoidosis, (13) genital and reproductive conditions,including erectile dysfunction; (14) gastrointestinal disorders,including gastritis, ulcers, nausea, pancreatitis, and vomiting; (15)neurologic disorders, including Alzheimer's disease; (16) sleepdisorders, including insomnia, narcolepsy, sleep apnea syndrome, andPickwick Syndrome; (17) pain; (18) renal disorders; (19) oculardisorders, including glaucoma; and (20) infectious diseases, includingHIV.

In certain embodiments, the disease is selected from the groupconsisting of asthma, allergic asthma, exercise induced asthma, allergicrhinitis, perennial allergic rhinitis, seasonal allergic rhinitis,atopic dermatitis, contact hypersensitivity, contact dermatitis,conjunctivitis, allergic conjunctivitis, eosinophilic bronchitis, foodallergies, eosinophilic gastroenteritis, inflammatory bowel disease,ulcerative colitis, Crohn's disease, mastocytosis, hyper IgE syndrome,systemic lupus erythematous, psoriasis, acne, multiple sclerosis,allograft rejection, reperfusion injury, chronic obstructive pulmonarydisease, Churg-Strauss syndrome, sinusitis, basophilic leukemia, chronicurticaria, basophilic leukocytosis, psoriasis, eczema, COPD (chronicobstructive pulmonary disorder), arthritis, rheumatoid arthritis,psoriatic arthritis, and osteoarthritis.

In certain embodiments, the disease is asthma, exercise induced asthma,allergic rhinitis, atopic dermatitis, chronic obstructive plumonarydisease, or allergic conjunctivitis.

In certain embodiments, the disease is Churg-Strauss syndrome orsinusitis.

Depending on the disease to be treated and the subject's condition, thecompounds or compositions provided herein may be administered by oral,parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV,intracistemal injection or infusion, subcutaneous injection, orimplant), inhalation, nasal, vaginal, rectal, sublingual, or topical(e.g., transdermal or local) routes of administration and may beformulated, alone or together, in suitable dosage unit withpharmaceutically acceptable carriers, adjuvants and vehicles appropriatefor each route of administration. Also provided is the administration ofthe compounds provided herein in a depot formulation, in which theactive ingredient is released over a predefined time period.

In the treatment, prevention, or amelioration of one or more symptoms ofasthma, exercise induced asthma, allergic rhinitis, eczema, psoriasis,atopic dermatitis, fever, sepsis, systemic lupus erythematosus,diabetes, rheumatoid arthritis, multiple sclerosis, atherosclerosis,transplant rejection, inflammatory bowel disease, cancer, or otherconditions, disorders or diseases associated with CRTH2 and/or one ormore other PGD₂ receptors, an appropriate dosage level generally isabout 0.001 to 100 mg per kg patient body weight per day (mg/kg perday), about 0.01 to about 75 mg/kg per day, about 0.1 to about 50 mg/kgper day, about 0.5 to about 25 mg/kg per day, or about 1 to about 20mg/kg per day, which may be administered in single or multiple doses.Within this range the dosage may be 0.005 to 0.05, 0.05 to 0.5, or 0.5to 5.0, 1 to 15, 1 to 20, or 1 to 50 mg/kg per day. In certainembodiments, the dosage level is about 0.001 to 100 mg/kg per day. Incertain embodiments, the dosage level is about 0.01 to about 75 mg/kgper day. In certain embodiments, the dosage level is about 0.1 to about50 mg/kg per day. In certain embodiments, the dosage level is about 0.5to about 25 mg/kg per day. In certain embodiments, the dosage level isabout 1 to about 20 mg/kg per day.

For oral administration, the pharmaceutical compositions can be providedin the form of tablets containing 1.0 to 1,000 mg of the activeingredient, particularly about 1, about 5, about 10, about 15, about 20,about 25, about 50, about 75, about 100, about 150, about 200, about250, about 300, about 400, about 500, about 600, about 750, about 800,about 900, and about 1,000 mg of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated. Thecompositions may be administered on a regimen of 1 to 4 times per day,including once, twice, three times, and four times per day.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

Combination Therapy

Also provided is a method of modulating CRTH2 and/or one or more otherPGD₂ receptors, comprising contacting the receptor(s) with one or moreof the compounds or compositions provided herein. In one embodiment, thereceptor(s) are expressed by a cell.

The compounds provided herein may also be combined or used incombination with other agents useful in the treatment, prevention, oramelioration of one or more symptoms of the diseases or conditions forwhich the compounds provided herein are useful, including asthma,exercise induced asthma, allergic rhinitis, eczema, psoriasis, atopicdermatitis, fever, sepsis, systemic lupus erythematosus, diabetes,rheumatoid arthritis, multiple sclerosis, atherosclerosis, transplantrejection, inflammatory bowel disease, cancer, and those pathologiesnoted above.

Other active agents to be used in combination with the compoundsprovided herein include, but are not limited to: inactivating antibodies(e.g., monoclonal or polyclonal) to interleukins (e.g., IL-4 and IL-5(for example see Leckie et al. 2000 Lancet 356:2144)); soluble chemokinereceptors (e.g. recombinant soluble IL-4 receptor (Steinke and Borish2001 Respiratory Research 2:66)); chemokine receptor modulatorsincluding but not limited to antagonists of CCR1 (e.g., CP-481,715(Gladue et al. J Biol Chem 278:40473)), CCR3 (e.g., UCB35625 (Sabroe etal. J Biol Chem 2000 275:25985) and CCR5; histamine H1 receptorantagonists/antihistamines (i.e. any compound that is capable ofblocking, inhibiting, reducing or otherwise interrupting the interactionbetween histamine and its receptor) including but not limited to:asternizole, acrivastine, antazoline, asternizole, azatadine,azelastine, bromopheniramine, carbinoxamine, carebastine, cetirizine,chlorpheniramine, clemastine, cyclizine, cyproheptadine,descarboethoxyloratadine, dexchlorpheniramine, dimethindene,diphenhydramine, diphenylpyraline, doxylamine, ebastine, efletirizine,epinastine, fexofenadine, hydroxyzine, hydroxyzine, ketotifen,levocabastine, levocetirizine, levocetirizine, loratadine, meclizine,mequitazine, methdilazine, mianserin, mizolastine, noberastine,norasternizole, noraztemizole, pheniramine, picumast, promethazine,pyrilamine, temelastine, terfenadine, trimeprazine, tripelenamine, andtriprolidin; leukotriene D4 receptor antagonists/leukotrieneantagonists/LTD4 antagonists (i.e., any compound that is capable ofblocking, inhibiting, reducing or otherwise interrupting the interactionbetween leukotrienes and the Cys LTI receptor) including but not limitedto: zafirlukast, montelukast, montelukast sodium (Singulair®),pranlukast, iralukast and pobilukast; PGD2 receptor antagonistsincluding, but not limited to, compounds having PGD2 antagonizingactivity; VLA-4 antagonists; corticosteroids, such as beclomethasone,methylprednisolone, betamethasone, prednisone, prenisolone,triamcinolone, dexamethasone, fluticasone, flunisolide andhydrocortisone, and corticosteroid analogs such as budesonide;immunosuppressants such as cyclosporine (cyclosporine A, Sandimmune®Neoral®), tacrolimus (FK-506, Prograf®), rapamycin (sirolimus,Rapamune®) and other FK-506 type immunosuppressants, and mycophenolate,e.g., mycophenolate mofetil (CellCept®); non-steroidal anti-asthmaticssuch as .beta.2-agonists (e.g., terbutaline, metaproterenol, fenoterol,isoetharine, albuterol, salmeterol, bitolterol and pirbuterol) and.beta.2-agonist-corticosteroid combinations (e.g.,salmeterol-fluticasone (Advair®), formoterol-budesonid (Symbicort®)),theophylline, cromolyn, cromolyn sodium, nedocromil, atropine,ipratropium, ipratropium bromide, leukotriene biosynthesis inhibitors(zileuton, BAY1005); non-steroidal antiinflammatory agents (NSAIDs) suchas propionic acid derivatives (e.g., alminoprofen, benoxaprofen,bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen,ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin,pirprofen, pranoprofen, suprofen, tiaprofenic acid and tioxaprofen),acetic acid derivatives (e.g., indomethacin, acemetacin, alclofenac,clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac,ibufenac, isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacinand zomepirac), fenamic acid derivatives (e.g., flufenamic acid,meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid),biphenylcarboxylic acid derivatives (e.g., diflunisal and flufenisal),oxicams (e.g., isoxicam, piroxicam, sudoxicam and tenoxican),salicylates (e.g., acetyl salicylic acid and sulfasalazine) and thepyrazolones (e.g., apazone, bezpiperylon, feprazone, mofebutazone,oxyphenbutazone and phenylbutazone); cyclooxygenase-2 (COX-2) inhibitorssuch as celecoxib (Celebrex®), rofecoxib (Vioxx®), valdecoxib,etoricoxib, parecoxib and lumiracoxib; inhibitors of phosphodiesterasetype IV (PDE-I); opioid analgesics such as codeine, fentanyl,hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone,oxymorphone, propoxyphene, buprenorphine, butorphanol, dezocine,nalbuphine and pentazocine; antithrombotic agents, such as thrombolyticagents (e.g., streptokinase, alteplase, anistreplase and reteplase),heparin, hirudin and warfarin derivatives, .beta.-blockers (e.g.,atenolol), .beta.-adrenergic agonists (e.g., isoproterenol), ACEinhibitors and vasodilators (e.g., sodium nitroprusside, nicardipinehydrochloride, nitroglycerin and enaloprilat); anti-diabetic agents suchas insulin and insulin mimetics, insulin derivatives such as, forexample, Lantus®, sulfonylureas (e.g., glyburide, meglinatide,tolbutamide, glibenclamide, glipizide or glimepiride), biguanides, e.g.,metformin (Glucophage®), meglitinides (for example, repaglinide),oxadiazolidinediones, glucosidase inhibitors (for example, miglitol oracarbose), insulin sensitizers, including but not limited tothiazolidinone compounds (for example, rosiglitazone (Avandia®),troglitazone (Rezulin®), ciglitazone, pioglitazone (Actos®) andenglitazone); glucagon antagonists; GLP-1 agonists; exendin-4;exenatine; potassium channel openers; HMGCoA reductase inhibitors (forexample, simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatinand cerivastatin); cholesterol absorption inhibitors (for example,ezetimibe, tiqueside and pamaqueside); fibrates such as, for example,fenofibrate, clofibrate and bezafibrate; rosuvastatin preparations ofinterferon beta (interferon .beta.-I.alpha., interferon .beta.-I.beta.);gold compounds such as auranofin and aurothioglucose; TNF inhibitors,e.g., etanercept (Enbrel®), antibody therapies such as orthoclone(OKT3), daclizumab (Zenapax®), basiliximab (Simulec®)), infliximab(Remicade®) and D2E6 TNF antibody; lubricants or emollients such aspetrolatum and lanolin, keratolytic agents, vitamin D.sub.3 derivatives(e.g., calcipotriene and calcipotriol (Dovonex®)), PUVA, anthralin(Drithrocreme®), etretinate (Tegison®) and isotretinoin; multiplesclerosis therapeutic agents such as interferon .beta.-I.beta.(Betaseron®), interferon .beta.-I.alpha. (Avonex®), azathioprine(Imurek®, Imuran®), glatiramer acetate (Capoxone®), a glucocorticoid(e.g., prednisolone) and cyclophosphamide; and other compounds such as5-aminosalicylic acid and prodrugs thereof DNA-alkylating agents (e.g.,cyclophosphamide, ifosfamide), antimetabolites (e.g., azathioprine,6-mercaptopurine, methotrexate, a folate antagonist, and 5-fluorouracil,a pyrimidine antagonist), microtubule disruptors (e.g., vincristine,vinblastine, paclitaxel, colchicine, nocodazole and vinorelbine), DNAintercalators (e.g., doxorubicin, daunomycin and cisplatin), DNAsynthesis inhibitors such as hydroxyurea, DNA cross-linking agents,e.g., mitomycin C, hormone therapy (e.g., tamoxifen, and flutamide), andcytostatic agents, e.g., imatinib (ST1571, Gleevec®) and rituximab(Rituxan®).

In another embodiment, the compounds provided herein can be administeredin combination with an MTP inhibitor such as, for example, implitapide,BMS-201038, R-103757. In another embodiment, the compounds providedherein can be administered in combination with bile acid absorptioninhibitor (see, for example, U.S. Pat. No. 6,245,744 or U.S. Pat. No.6,221,897), such as, for example, HMR 1741; a CETP inhibitor, such as,for example, JTF-705; a polymeric bile acid adsorbent such as, forexample, cholestyramine, colesevelam; an LDL receptor inducer (see U.S.Pat. No. 6,342,512), such as, for example, HMR1171, HMR1586; an ACATinhibitor, such as, for example, avasimibe; an antioxidant, such as, forexample, OPC-14117; a lipoprotein lipase inhibitor, such as, forexample, NO-1886; an ATP-citrate lyase inhibitor, such as, for example,SB-204990; a squalene synthetase inhibitor, such as, for example,BMS-188494; a lipoprotein(a) antagonist, such as, for example, CI-1027;nicotinic acid; a lipase inhibitor, such as, for example, orlistat(Xenical®, Alli); immunosuppressant drugs, such as, cyclosporin A,substituted xanthines (e.g. methylxanthines such as pentoxyfylline),tacrolimus, rapamycin (and derivatives thereof), leflunomide (or itsmain active metabolite A771726, or analogs thereof calledmalononitrilamides), mycophenolic acid and salts thereof (including thesodium salt marketed under the trade name Mofetil®), adrenocorticalsteroids (for example, dexamethasone, methylprednisolone, methotrexate,prednisone, prednisolone, triamcinolone and pharmaceutically acceptablesalts thereof), azathioprine, brequinar, gusperimus, 6-mercaptopurine,mizoribine, chloroquine, hydroxychloroquine and monoclonal antibodieswith immunosuppressive properties; immunomodulators, such as, acemannan,amiprilose, bucillamine, ditiocarb sodium, imiquimod, inosinepranobex(Isoprinosine®, Immunovir®, Delimmun®), interferon-.beta.,interferon-.gamma., lentinan, levamisole, pidotimod, romurtide,platonin, procodazole, propagermanium, thymomodulin, thymopentin andubenimex.

In another embodiment, the compounds provided herein can be administeredin combination with an agent used to treat asthma or exercise inducedasthma, including, but not limited to: albuterol (Accuneb®, ProAir HFA®,Proventil®, Ventolin®, Vospire®), beclomethasone (Qvar®), budesonide(Pulmicort®), cromolyn (Intal®), terbutaline (Brethine®), metaproterenol(Alupent®), theophylline (Quibron-T®, Elixophyllin®, Uniphyl®),theophylline ethylenediamine (Aminophylline®), ephedrine, epinephrine,flunisolide (Aerobid®), fluticasone (Flovent®), levabuterol (Xopenex®),mometazone (Asmanex®), montelukast sodium (Singulair®), nedocromil(Tilade®), triamcinolone (Azmacort®), fenoterol, isoetharine,salmeterol, bitolterol, dyphylline (Dilor®, Dylix®, Lufyllin®),dyphylline/guaifenesin (COPD®, Lufyllin-GG®, Ed-Bron G®), PrimateneAsthma®, pirbuterol (Maxair®), zafirlukast (Accolate®) or zileuton(Zyflo®).

In another embodiment, the compounds provided herein can be administeredin combination with an agent used to treat multiple sclerosis,including, but not limited to: betamethasone (Celestone®),hydrocortisone (A-Hydrocort®, Cortef®), hydrocortisone sodium succinate(Solu-Cortef®), corticotropin (Acthar®), methylprednisolone(A-Methapred®, Medrol®, Depo-Medrol®, Meprolone®), methylprednisolonesodium succinate (Solu-Medrol®), dexamethasone (DexPak®, Dexacort®),triamcinolone (Kenalog®), triamcinolone acetonide, prednisolone(Prelone®, Orapred®, Sterapred®, Pediapred®), interferon beta-1a(Avonex®, Rebif®), interferon beta-1b (Betaseron®), baclofen (Kemstro®,Lioresal®), glatiramer (Copaxone®), dantrolene sodium (Dantrium®),mitoxantrone, mitoxantrone hydrochloride (Novantrone®), natalizumab(Tysabri®), tizanidine (Zanaflex®, Sirdalud®), amantadine, clostridiumbotulinum toxin (Botox®), cyclophosphamide (Neosar®, Cytoxan®) orcycloheptadine.

In another embodiment, the compounds provided herein can be administeredin combination with an agent used to treat inflammatory bowel disease,including, but not limited to: adalimumab (Humria®), loperamide(Diamode®, Immodium®, Kaopectate 1-D®, Maalox®, Imperim®, Pepto DiarrheaControl®), azathioprine (Imuran®), betamethasone (Celestone®),hydrocortisone (A-Hydrocort®, Cortef®), corticotropin (Acthar®),methylprednisolone (A-Methapred®, Medrol®, Depo-Medrol®, Meprolone®),dexamethasone (DexPak®, Dexacort®), osalazine (Dipentum®), cromolyn(Gastrocrom®), triamcinolone (Kenalog®, Aristocort®, Triacet®),mercaptopurine (Purinethol®) or prednisolone (Prelone®, Orapred®,Sterapred®, Pediapred®).

In another embodiment, the compounds provided herein can be administeredin combination with an agent used to treat transplant rejection,including, but not limited to: betamethasone (Celestone®),hydrocortisone (A-Hydrocort®, Cortef®), corticotropin (Acthar®),methylprednisolone (A-Methapred®, Medrol®, Depo-Medrol®, Meprolone®),dexamethasone (DexPak®, Dexacort®), triamcinolone (Kenalog®,Aristocort®, Triacet®), cyclosporine (Neoral®, Sandimmune®, Gengraf®),muromonab (Orthoclone OKT3®), tacrolimus (Prograf®) or prednisolone(Prelone®, Orapred®, Sterapred®, Pediapred®).

Such other agents, or drugs, may be administered, by a route and in anamount commonly used therefor, simultaneously or sequentially with acompound or composition provided herein. When a compound provided hereinis used contemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compoundprovided herein may be utilized, but is not required. Accordingly, thepharmaceutical compositions provided herein include those that alsocontain one or more other active ingredients or therapeutic agents, inaddition to a compound provided herein.

The weight ratio of the compound provided herein to the second activeingredient may be varied, and will depend upon the effective dose ofeach ingredient. Generally, an effective dose of each will be used.Thus, for example, when a compound provided herein is combined with aNSAID, the weight ratio of the compound provided herein to the NSAID mayrange from about 1,000:1 to about 1:1,000, or about 200:1 to about1:200. Combinations of a compound provided herein and other activeingredients will generally also be within the aforementioned range, butin each case, an effective dose of each active ingredient should beused.

EXAMPLES Synthesis of2-(4-chloro-6-(dimethylamino)-2-(4-(4-(trifluoromethyl)-benzamido)benzylthio)pyrimidin-5-yl)aceticacid (5) and2-(4-chloro-6-(dimethylamino)-2-(4-(4-fluorobenzamido)benzylthio)pyrimidin-5-yl)aceticacid (6)

Methyl 2-(4,6-dichloro-2-(4-nitrobenzylthio)pyrimidin-5-yl)acetate (1)was prepared by methods known in the art, for example, the processdescribed in GB 2,359,078.

Preparation of methyl2-(4-chloro-6-(dimethylamino)-2-(4-nitrobenzylthio)-pyrimidin-5-yl)acetate(2). To a solution of 1 (0.37 g) in tetrahydrofuran (5.00 mL) at roomtemperature was added potassium carbonate (0.66 g) and dimethylaminehydrochloride (0.09 g). The resulting suspension was stirred at roomtemperature for 16 hours and filtered. The remaining residue was rinsedwith ethyl acetate and the filtrate was washed sequentially with 1N HCl,water, and brine, dried over anhydrous magnesium sulfate, filtered, andconcentrated in vacuo. The crude product thus obtained as a dark oil waspurified by flash chromatography over silica gel eluting with 25% ethylacetate in hexanes to give pure compound 2 as a white powder (0.20 g).

Preparation of methyl2-(2-(4-aminobenzylthio)-4-chloro-6-(dimethylamino)-pyrimidin-5-yl)acetate(3). To a suspension of 2 (1.11 g) in ethanol (25 mL0 at roomtemperature was added tin(II) chloride dehydrate (3.81 g) and theresulting mixture was refluxed for 2 hours. After cooling to rt, thevolume was reduce by approximately half by concentration in vacuo andthe remaining clear yellow solution was poured into chilled saturatedsodium bicarbonate solution. The resulting white suspension was treatedwith EtOAc and filtered through Celite. The filtrate was allowed toseparate and the aqueous layer was extracted with EtOAc thrice. Thecombined organic extracts was washed with water and brine, dried overanhydrous MgSO4, filtered, and concentrated in vacuo to give crude 3 asan orange oil (1.12 g).

Preparation of2-(4-chloro-6-(dimethylamino)-2-(4-(4-(trifluoromethyl)benzamido)benzylthio)pyrimidin-5-yl)aceticacid (5). To a solution of 3 (0.10 g) and triethylamine (0.12 mL) indichloromethane (2 mL) chilled in an ice-bath was added4-trifluoromethylbenzoyl chloride (0.05 mL). The ice-bath was removedand the reaction mixture was allowed to warm to room temperature. Afterstirring at room temperature for 1 hour, the reaction mixture waspartitioned between dichloromethane and 1N HCl solution. The separatedorganic layer was washed with water and brine, dried over anhydrousmagnesium sulfate, filtered, and concentrated in vacuo. The crudeproduct thus obtained as a white powder was triturated withdiisopropylether and filtered to give compound 4 as a white powder (0.16g) which was dissolved in tetrahydrofuran (4.00 mL) and treated with 1NNaOH solution (1.00 mL). Methanol was introduced dropwise until ahomogeneous reaction mixture was achieved. After stirring at roomtemperature for 16 hours, the volatiles were removed in vacuo and theremaining white suspension was diluted with some water, treated withdiethylether, stirred vigorously for 1 minute, and allowed to separate.The separated organic layer was decanted and the remaining aqueoussuspension was chilled in an ice-bath and carefully acidified to pH˜4.The separated solids were collected by suction and rinsed with water anddried to furnish compound 5 as a white powder (0.11 g).

Preparation of2-(4-chloro-6-(dimethylamino)-2-(4-(4-fluorobenzamido)benzylthio)pyrimidin-5-yl)aceticacid (6)

A solution of 3 (0.10 g) in dichloromethane (2.00 mL) at roomtemperature was treated with 4-fluorobenzoic acid (0.06 g),triethylamine (0.07 mL), and 4-dimethylaminopyridine (0.04 g). When allsolids have dissolved, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (0.11 g) was added. After stirring at room temperature for16 hours, the reaction mixture was partitioned between dichloromethaneand 1N HCl solution, the separated organic layer was collected andwashed sequentially with water and brine, dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo to give a light green oilfrom which the crude methyl ester intermediate (0.09 g) was obtained asa white powder by trituration with dichloromethane and diisopropylether.Hydrolysis of the intermediate using the same procedure as detailedabove gave compound 6 as a white powder (0.07 g).

1. A compound having the formula I:

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer ortautomer thereof, wherein R¹ is —CO₂R⁹, —C(O)NR^(8a)R^(8b), nitrile ortetrazolyl; R^(4a) and R^(4b) are each independently hydrogen or(C₁-C₆)alkyl; in each instance, independently, W, R², R³, R⁵, R^(5a),R⁶, R⁷, R^(8a), R^(8b), R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, m and n areselected from (I) or (II) as follows: (I) W is a single bond,—(CH₂)_(m)—, —O—, —S(O)_(n)—, —NR⁷—, —C(O)—, —C(O)O—, —C(O)NR⁷—,—NR⁷C(O)NR⁷— or —NR⁷C(O)O—; in each instance, independently, R² and R³are selected from (i) or (ii) as follows: (i) R² and R³ are eachindependently (a) hydrogen; (b) F; (c) Br; (d) I; (e) (C₁-C₆)alkyl; (f)(C₁-C₆)alkyl substituted by aryl, hydroxy, carboxy, alkoxy, carbamoyl,(C₁-C₆)alkylcarbamoyl, di(C₁-C₆)alkyl)carbamoyl,(C₃-C₇)cycloalkylcarbamoyl or (C₃-C₇)heterocyclylcarbamoyl; (g)(C₁-C₆)alkyl substituted by mono-, di-, or tri-halogen; (h)(C₃-C₇)cycloalkyl; (i) —SR⁹; (j) —NR¹⁰R¹¹; or (k) (C₁-C₆)alkoxyoptionally substituted by mono-, di-, or tri-halogen; or (ii) R² and R³are each independently (a) hydrogen: (b) Cl; (c) (C₁-C₆)alkyl; (d)(C₁-C₆)alkyl substituted by aryl, hydroxy, carboxy, alkoxy, carbamoyl,(C₁-C₆)alkylcarbamoyl, di(C₁-C₆)alkyl)carbamoyl,(C₃-C₇)cycloalkylcarbamoyl or (C₃-C₇)heterocyclylcarbamoyl; (e)(C₁-C₆)alkyl substituted by mono-, di-, or tri-halogen; (f)(C₃-C₇)cycloalkyl; (g) —SR⁹; (h) —NR¹²R¹³; or (i) (C₁-C₆)alkoxyoptionally substituted by mono-, di-, or tri-halogen; R⁵ is (a)hydrogen; (b) halogen; (c) cyano; (d) nitro; (e) hydroxy; (f) phenyl;(g) phenyloxy; (h) benzyl; (i) benzyloxy; (j) guanidino; (k)heterocyclyl; (l) —NR¹⁴R¹⁵; (m) sulfamoyl; (n) (C₁-C₆)alkylsulfonyl; (o)(C₁-C₆)alkylaminosulfonyl; (p) di(C₁-C₆)alkylaminosulfonyl; (q) —C(O)R⁹;(r) —C(O)OR⁹; (s) —C(O)NR^(8a)R^(8b); (t) —NR⁷C(O)R⁹; (u)—OC(O)NR^(8a)R^(8b); (v) —NR⁷C(O)OR⁹; (w) (C₂-C₆)alkenyl; (x)(C₁-C₆)alkyl optionally substituted by mono-, di-, or tri-halogen; (y)(C₁-C₆)alkoxy optionally substituted by mono-, di-, or tri-halogen; or(z) (C₁-C₆)alkylthio optionally substituted by mono-, di-, ortri-halogen; R⁶ is (a) hydrogen; (b) (C₁-C₆)alkyl; (c) (C₂-C₆)alkenyl;(d) (C₂-C₆)alkynyl; (e) (C₃-C₇)cycloalkyl; (f) (C₁-C₆)alkyl substitutedby aryl or heteroaryl; (g) (C₂-C₄)alkenyl substituted by aryl orheteroaryl; (h) (C₁-C₆)alkyl substituted by mono-, di-, or tri-halogen;(i) (C₁-C₆)alkyl substituted by —C(O)R^(6a); (j) (C₁-C₆)alkoxysubstituted by mono-, di-, or tri-halogen; (k) (C₁-C₆)alkylthiosubstituted by mono-, di-, or tri-halogen; (l) aryl; (m) or heteroaryl,wherein said aryl and heteroaryl are optionally substituted at asubstitutable position with one or more substituents selected from thegroup consisting of (a) halogen; (b) cyano; (c) nitro; (d) hydroxy; (e)guanidino; (t) heterocyclyl; (g) phenyl; (h) phenyloxy; (i) benzyl; (j)benzyloxy; (k) —NR^(8a)R^(8b); (l) —C(O)R⁹; (m) —C(O)NR^(8a)R^(8b); (n)—OC(O)NR^(8a)R^(8b); (o) —C(O)OR⁹; (p) —NR⁷C(O)OR⁹; (q) —NR⁷C(O)R⁹; (r)sulfamoyl; (s) (C₁-C₆)alkylsulfonyl; (t) (C₁-C₆)alkylaminosulfonyl; (u)di(C₁-C₆)alkylaminosulfonyl; (v) (C₁-C₆)alkyl optionally substituted bymono-, di-, or tri-halogen; (w) (C₁-C₆)alkoxy optionally substituted bymono-, di-, or tri-halogen; and (x) (C₁-C₆)alkylthio optionallysubstituted by mono-, di-, or tri-halogen; R^(6a) is (a) hydrogen; (b)(C₁-C₆)alkyl; (c) (C₂-C₆)alkenyl; (d) (C₂-C₆)alkynyl; (e)(C₃-C₇)cycloalkyl; (t) (C₁-C₆)alkyl substituted by aryl or heteroaryl;(g) (C₂-C₄)alkenyl substituted by aryl or heteroaryl; (h) (C₁-C₆)alkylsubstituted by mono-, di-, or tri-halogen; (i) (C₁-C₆)alkoxy substitutedby mono-, di-, or tri-halogen; (j) (C₁-C₆)alkylthio substituted bymono-, di-, or tri-halogen; (k) aryl; (l) or heteroaryl, wherein saidaryl and heteroaryl are optionally substituted at a substitutableposition with one or more substituents selected from the groupconsisting of (a) halogen; (b) cyano; (c) nitro; (d) hydroxy; (e)guanidino; (f) heterocyclyl; (g) phenyl; (h) phenyloxy; (i) benzyl; (j)benzyloxy; (k) —NR^(8a)R^(8b); (l) —C(O)R⁹; (m) —C(O)NR^(8a)R^(8b); (n)—OC(O)NR^(8a)R^(8b); (o) —C(O)OR⁹; (p) —NR⁷C(O)OR⁹; (q) —NR⁷C(O)R⁹; (r)sulfamoyl; (s) (C₁-C₆)alkylsulfonyl; (t) (C₁-C₆)alkylaminosulfonyl; (u)di(C₁-C₆)alkylaminosulfonyl; (v) (C₁-C₆)alkyl optionally substituted bymono-, di-, or tri-halogen; (w) (C₁-C₆)alkoxy optionally substituted bymono-, di-, or tri-halogen; and (x) (C₁-C₆)alkylthio optionallysubstituted by mono-, di-, or tri-halogen; R⁷ is (a) hydrogen; (b)(C₁-C₆)alkyl; (c) phenyl; (d) (C₁-C₆)alkyl substituted by aryl, hydroxy,carboxy, alkoxy, carbamoyl, (C₁-C₆)alkylcarbamoyl,di((C₁-C₆)alkyl)carbamoyl, (C₃-C₇)cycloalkylcarbamoyl or(C₃-C₇)heterocyclylcarbamoyl; (e) (C₁-C₆)alkyl substituted by mono-,di-, or tri-halogen; or (f) (C₃-C₇)cycloalkyl; in each instance,independently, R^(8a) and R^(9b) are selected from (i) or (ii) asfollows: (i) R^(8a) and R^(8b) are each independently selected from (a)hydrogen; (b) (C₁-C₆)alkyl; (c) phenyl; (d) (C₁-C₆)alkyl substituted byaryl, hydroxy, carboxy, alkoxy, carbamoyl, (C₁-C₆)alkylcarbamoyl,di((C₁-C₆)alkyl)carbamoyl, (C₃-C₇)cycloalkylcarbamoyl or(C₃-C₇)heterocyclylcarbamoyl; (e) (C₁-C₆)alkyl substituted by mono-,di-, or tri-halogen; or (f) (C₃-C₇)cycloalkyl; or (ii) each R^(8a) andR^(8b), together with the N to which they are bonded, independently mayform a 3 to 8 membered saturated or unsaturated ring optionallycontaining one or more O or S atoms, or one or more additional N atoms,in the ring; each R⁹ is independently (a) hydrogen; (b) (C₁-C₆)alkyl;phenyl; or (c) (C₁-C₆)alkyl substituted by aryl, alkoxy or mono-, di-,or tri-halogen; in each instance, independently, R¹⁰ and R¹¹ areselected from (i) or (ii) as follows: (i) R¹⁹ and R¹¹ are eachindependently selected from (a) hydrogen; (b) (C₁-C₆)alkyl; (c) phenyl;(d) (C₁-C₆)alkyl substituted by aryl, hydroxy, carboxy, alkoxy,carbamoyl, (C₁-C₆)alkylcarbamoyl, di((C₁-C₆)alkyl)carbamoyl,(C₃-C₇)cycloalkylcarbamoyl or (C₃-C₇)heterocyclylcarbamoyl; (e)(C₁-C₆)alkyl substituted by mono-, di-, or tri-halogen; or (f)(C₃-C₇)cycloalkyl; or (ii) each R¹⁰ and R¹¹, together with the N towhich they are bonded, independently may form a 3 to 8 memberedsaturated or unsaturated ring optionally containing one or more O or Satoms, or one or more additional N atoms, in the ring; in each instance,independently, R¹² and R¹³ are selected from (i), (ii), (iii) or (iv) asfollows: (i) R¹² and R¹³ are each independently selected from (a)hydrogen; (b) (C₁-C₆)alkyl; (c) phenyl; (d) (C₁-C₆)alkyl substituted byaryl, hydroxy, carboxy or alkoxy; (e) (C₁-C₆)alkyl substituted by mono-,di-, or tri-halogen; or (f) (C₃-C₇)cycloalkyl; (ii) R¹² and R¹³,together with the N to which they are bonded, form a 5 memberedsaturated ring containing at least one O or S atom, or at least oneadditional N atom, in the ring; (iii) R¹² and R¹³, together with the Nto which they are bonded, form a 5 membered unsaturated ring, optionallycontaining one or more O or S atom, or one or more additional N atoms,in the ring; or (iv) R¹² and R¹³, together with the N to which they arebonded, form a 3, 4, 6, 7 or 8 membered saturated or unsaturated ring,optionally containing one or more O or S atoms, or one or moreadditional N atoms, in the ring; in each instance, independently, R¹⁴and R¹⁵ are selected from (i) or (ii) as follows: (i) R¹⁴ and R¹⁵ areeach independently selected from (a) hydrogen; (b) (C₁-C₆)alkyl; (c)phenyl; (d) (C₁-C₆)alkyl substituted by aryl, hydroxy, carboxy, alkoxy,carbamoyl, (C₁-C₆)alkylcarbamoyl, di((C₁-C₆)alkyl)carbamoyl,(C₃-C₇)cycloalkylcarbamoyl or (C₃-C₇)heterocyclylcarbamoyl; (e)(C₁-C₆)alkyl substituted by mono-, di-, or tri-halogen; or (f)(C₃-C₇)cycloalkyl; or (ii) each R¹⁴ and R¹⁵, together with the N towhich they are bonded, independently may form a 3 to 8 memberedsaturated or unsaturated ring optionally containing one or more O or Satoms, or one or more additional N atoms, in the ring; k is 0, 1 or 2; mis 1, 2, 3 or 4; n is 0, 1 or 2; or (II) R⁵ and W—R⁶ together with theatom to which they are attached may form a 4 to 8 membered unsaturatedring optionally containing one or more N, O or S atoms in the ring,wherein the ring is optionally substituted with one or more R^(5a)groups; R² and R³ are each independently (a) hydrogen; (b) F; (c) Cl;(d) Br; (e) I; (0 (C₁-C₆)alkyl; (g) (C₁-C₆)alkyl substituted by aryl,hydroxy, carboxy, alkoxy, carbamoyl, (C₁-C₆)alkylcarbamoyl,di(C₁-C₆)alkyl)carbamoyl, (C₃-C₇)cycloalkylcarbamoyl or(C₃-C₇)heterocyclylcarbamoyl; (h) (C₁-C₆)alkyl substituted by mono-,di-, or tri-halogen; (i) (C₃-C₇)cycloalkyl; (j) —SR⁹; (k) —NR¹⁰R¹¹; or(l) (C₁-C₆)alkoxy optionally substituted by mono-, di-, or tri-halogen;R⁵ and R^(5a) are each independently (a) hydrogen; (b) halogen; (c)cyano; (d) nitro; (e) hydroxy; (f) phenyl; (g) phenyloxy; (h) benzyl;(i) benzyloxy; (j) guanidino; (k) heterocyclyl; (l) —NR¹⁴R¹⁵; (m)sulfamoyl; (n) (C₁-C₆)alkylsulfonyl; (o) (C₁-C₆)alkylaminosulfonyl; (p)di(C₁-C₆)alkylaminosulfonyl; (q) —C(O)R⁹; (r) —C(O)OR⁹; (s)—C(O)NR^(8a)R^(8b); (t) —NR⁷C(O)R⁹; (u) —OC(O)NR^(8a)R^(8b); (v)—NR⁷C(O)OR⁹; (w) (C₂-C₆)alkenyl; (x) (C₁-C₆)alkyl optionally substitutedby mono-, di-, or tri-halogen; (y) (C₁-C₆)alkoxy optionally substitutedby mono-, di-, or tri-halogen; or (z) (C₁-C₆)alkylthio optionallysubstituted by mono-, di-, or tri-halogen; R⁶ is (a) hydrogen; (b)(C₁-C₆)alkyl; (c) (C₂-C₆)alkenyl; (d) (C₂-C₆)alkynyl; (e)(C₃-C₇)cycloalkyl; (f) (C₁-C₆)alkyl substituted by aryl or heteroaryl;(g) (C₂-C₄)alkenyl substituted by aryl or heteroaryl; (h) (C₁-C₆)alkylsubstituted by mono-, di-, or tri-halogen; (i) (C₁-C₆)alkyl substitutedby —C(O)R^(6a); (j) (C₁-C₆)alkoxy substituted by mono-, di-, ortri-halogen; (k) (C₁-C₆)alkylthio substituted by mono-, di-, ortri-halogen; (l) aryl; (m) or heteroaryl, wherein said aryl andheteroaryl are optionally substituted at a substitutable position withone or more substituents selected from the group consisting of (a)halogen; (b) cyano; (c) nitro; (d) hydroxy; (e) guanidino; heterocyclyl;(g) phenyl; (h) phenyloxy; (i) benzyl; (j) benzyloxy; (k)—NR^(8a)R^(8b); (l) —C(O)R⁹; (m) —C(O)NR^(8a)R^(8b); (n)—OC(O)NR^(8a)R^(8b); (o) —C(O)OR⁹; (p) —NR⁷C(O)OR⁹; (q) —NR⁷C(O)R⁹; (r)sulfamoyl; (s) (C₁-C₆)alkylsulfonyl; (t) (C₁-C₆)alkylaminosulfonyl; (u)di(C₁-C₆)alkylaminosulfonyl; (v) (C₁-C₆)alkyl optionally substituted bymono-, di-, or tri-halogen; (w) (C₁-C₆)alkoxy optionally substituted bymono-, di-, or tri-halogen; and (x) (C₁-C₆)alkylthio optionallysubstituted by mono-, di-, or tri-halogen; R^(6a) is (a) hydrogen; (b)(C₁-C₆)alkyl; (c) (C₂-C₆)alkenyl; (d) (C₂-C₆)alkynyl; (e)(C₃-C₇)cycloalkyl; (C₁-C₆)alkyl substituted by aryl or heteroaryl; (g)(C₂-C₄)alkenyl substituted by aryl or heteroaryl; (h) (C₁-C₆)alkylsubstituted by mono-, di-, or tri-halogen; (i) (C₁-C₆)alkoxy substitutedby mono-, di-, or tri-halogen; (j) (C₁-C₆)alkylthio substituted bymono-, di-, or tri-halogen; (k) aryl; (l) or heteroaryl, wherein saidaryl and heteroaryl are optionally substituted at a substitutableposition with one or more substituents selected from the groupconsisting of (a) halogen; (b) cyano; (c) nitro; (d) hydroxy; (e)guanidino; (f) heterocyclyl; (g) phenyl; (h) phenyloxy; (i) benzyl; (j)benzyloxy; (k) —NR^(8a)R^(8b); (l) —C(O)R⁹; (m) —C(O)NR^(8a)R^(8b); (n)—OC(O)NR^(8a)R^(8b); (o) —C(O)OR⁹; (p) —NR⁷C(O)OR⁹; (q) —NR⁷C(O)R⁹; (r)sulfamoyl; (s) (C₁-C₆)alkylsulfonyl; (t) (C₁-C₆)alkylaminosulfonyl; (u)di(C₁-C₆)alkylaminosulfonyl; (v) (C₁-C₆)alkyl optionally substituted bymono-, di-, or tri-halogen; (w) (C₁-C₆)alkoxy optionally substituted bymono-, di-, or tri-halogen; and (x) (C₁-C₆)alkylthio optionallysubstituted by mono-, di-, or tri-halogen; R⁷ is (a) hydrogen; (b)(C₁-C₆)alkyl; (c) phenyl; (d) (C₁-C₆)alkyl substituted by aryl, hydroxy,carboxy, alkoxy, carbamoyl, (C₁-C₆)alkylcarbamoyl,di((C₁-C₆)alkyl)carbamoyl, (C₃-C₇)cycloalkylcarbamoyl or(C₃-C₇)heterocyclylcarbamoyl; (e) (C₁-C₆)alkyl substituted by mono-,di-, or tri-halogen; or (f) (C₃-C₇)cycloalkyl; in each instance,independently, R^(8a) and R^(8b) are selected from (i) or (ii) asfollows: (i) R^(8a) and R^(8b) are each independently selected from (a)hydrogen; (b) (C₁-C₆)alkyl; (c) phenyl; (d) (C₁-C₆)alkyl substituted byaryl, hydroxy, carboxy, alkoxy, carbamoyl, (C₁-C₆)alkylcarbamoyl,di((C₁-C₆)alkyl)carbamoyl, (C₃-C₇)cycloalkylcarbamoyl or(C₃-C₇)heterocyclylcarbamoyl; (e) (C₁-C₆)alkyl substituted by mono-,di-, or tri-halogen; or (f) (C₃-C₇)cycloalkyl; or (ii) each R^(8a) andR^(8b), together with the N to which they are bonded, independently mayform a 3 to 8 membered saturated or unsaturated ring optionallycontaining one or more O or S atoms, or one or more additional N atoms,in the ring; each R⁹ is independently (a) hydrogen; (b) (C₁-C₆)alkyl;phenyl; or (c) (C₁-C₆)alkyl substituted by aryl, alkoxy or mono-, di-,or tri-halogen; in each instance, independently, R¹⁰ and R¹¹ areselected from (i) or (ii) as follows: (i) R¹⁰ and R¹¹ are eachindependently selected from (a) hydrogen; (b) (C₁-C₆)alkyl; (c) phenyl;(d) (C₁-C₆)alkyl substituted by aryl, hydroxy, carboxy, alkoxy,carbamoyl, (C₁-C₆)alkylcarbamoyl, di((C₁-C₆)alkyl)carbamoyl,(C₃-C₇)cycloalkylcarbamoyl or (C₃-C₇)heterocyclylcarbamoyl; (e)(C₁-C₆)alkyl substituted by mono-, di-, or tri-halogen; or (f)(C₃-C₇)cycloalkyl; or (ii) each R¹⁰ and R¹¹, together with the N towhich they are bonded, independently may form a 3 to 8 memberedsaturated or unsaturated ring optionally containing one or more O or Satoms, or one or more additional N atoms, in the ring; k is 0, 1 or 2; mis 1, 2, 3 or 4; and n is 0, 1 or
 2. 2. The compound of claim 1 wherein,in each instance, independently, R¹⁰ and R¹¹ are selected from (i) or(ii) as follows: (i) R¹⁰ and R¹¹ are each independently selected from(a) hydrogen; (b) (C₁-C₆)alkyl; (c) phenyl; (d) (C₁-C₆)alkyl substitutedby unsubstituted phenyl, hydroxy, carboxy, alkoxy, carbamoyl,(C₁-C₆)alkylcarbamoyl, di((C₁-C₆)alkyl)carbamoyl,(C₃-C₇)cycloalkylcarbamoyl or (C₃-C₇)heterocyclylcarbamoyl; (e)(C₁-C₆)alkyl substituted by mono-, di-, or tri-halogen; or (f)(C₃-C₇)cycloalkyl; or (ii) each R¹⁰ and R¹¹, together with the N towhich they are bonded, independently may form a 3 to 8 memberedsaturated or unsaturated ring optionally containing one or more O or Satoms, or one or more additional N atoms, in the ring; and in eachinstance, independently, R¹² and R¹³ are selected from (i), (ii), (iii)or (iv) as follows: (i) R¹² and R¹³ are each independently selected from(a) hydrogen; (b) (C₁-C₆)alkyl; (c) phenyl; (d) (C₁-C₆)alkyl substitutedby unsubstituted phenyl, hydroxy, carboxy or alkoxy; (e) (C₁-C₆)alkylsubstituted by mono-, di-, or tri-halogen; or (f) (C₃-C₇)cycloalkyl;(ii) R¹² and R¹³, together with the N to which they are bonded, form a 5membered saturated ring containing at least one O or S atom, or at leastone additional N atom, in the ring; (iii) R¹² and R¹³, together with theN to which they are bonded, form a 5 membered unsaturated ring,optionally containing one or more O or S atom, or one or more additionalN atoms, in the ring; or (iv) R¹² and R¹³, together with the N to whichthey are bonded, form a 3, 4, 6, 7 or 8 membered saturated orunsaturated ring, optionally containing one or more O or S atoms, or oneor more additional N atoms, in the ring.
 3. The compound of claim 1wherein, in each instance, independently, R¹⁰ and R¹¹ are selected from(i) or (ii) as follows: (i) R¹⁰ and R¹¹ are each independently selectedfrom (a) hydrogen; (b) (C₁-C₆)alkyl; (c) phenyl; (d) (C₁-C₆)alkylsubstituted by hydroxy, carboxy, alkoxy, carbamoyl,(C₁-C₆)alkylcarbamoyl, di((C₁-C₆)alkyl)carbamoyl,(C₃-C₇)cycloalkylcarbamoyl or (C₃-C₇)heterocyclylcarbamoyl; (e)(C₁-C₆)alkyl substituted by mono-, di-, or tri-halogen; or (f)(C₃-C₇)cycloalkyl; or (ii) each R¹⁰ and R¹¹, together with the N towhich they are bonded, independently may form a 3 to 8 memberedsaturated or unsaturated ring optionally containing one or more O or Satoms, or one or more additional N atoms, in the ring; and in eachinstance, independently, R¹² and R¹³ are selected from (i), (ii), (iii)or (iv) as follows: (i) R¹² and R¹³ are each independently selected from(a) hydrogen; (b) (C₁-C₆)alkyl; (c) phenyl; (d) (C₁-C₆)alkyl substitutedby hydroxy, carboxy or alkoxy; (e) (C₁-C₆)alkyl substituted by mono-,di-, or tri-halogen; or (f) (C₃-C₇)cycloalkyl; (ii) R¹² and R¹³,together with the N to which they are bonded, form a 5 memberedsaturated ring containing at least one O or S atom, or at least oneadditional N atom, in the ring; (iii) R¹² and R¹³, together with the Nto which they are bonded, form a 5 membered unsaturated ring, optionallycontaining one or more O or S atom, or one or more additional N atoms,in the ring; or (iv) R¹² and R¹³, together with the N to which they arebonded, form a 3, 4, 6, 7 or 8 membered saturated or unsaturated ring,optionally containing one or more O or S atoms, or one or moreadditional N atoms, in the ring.
 4. The compound of claim 1 wherein, ineach instance, independently, R¹⁰ and R¹¹ are selected from (i) or (ii)as follows: (i) R¹⁰ and R¹¹ are each independently selected from (a)hydrogen; (b) (C₁-C₆)alkyl; (c) phenyl; (d) (C₁-C₆)alkyl substituted bymono-, di-, or tri-halogen; or (e) (C₃-C₇)cycloalkyl; or (ii) each R¹⁰and R¹¹, together with the N to which they are bonded, independently mayform a 3 to 8 membered saturated or unsaturated ring optionallycontaining one or more O or S atoms, or one or more additional N atoms,in the ring; and in each instance, independently, R¹² and R¹³ areselected from (i), (ii), (iii) or (iv) as follows: (i) R¹² and R¹³ areeach independently selected from (a) hydrogen; (b) (C₁-C₆)alkyl; (c)phenyl; (d) (C₁-C₆)alkyl substituted by mono-, di-, or tri-halogen; or(e) (C₃-C₇)cycloalkyl; (ii) R¹² and R¹³, together with the N to whichthey are bonded, form a 5 membered saturated ring containing at leastone O or S atom, or at least one additional N atom, in the ring; (iii)R¹² and R¹³, together with the N to which they are bonded, form a 5membered unsaturated ring, optionally containing one or more O or Satom, or one or more additional N atoms, in the ring; or (iv) R¹² andR¹³, together with the N to which they are bonded, form a 3, 4, 6, 7 or8 membered saturated or unsaturated ring, optionally containing one ormore O or S atoms, or one or more additional N atoms, in the ring. 5.The compound of claim 1 wherein R¹ is —CO₂H.
 6. The compound of claim 1wherein R^(4a) and R^(4b) are each independently hydrogen.
 7. Thecompound of claim 1, having formula II:

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer ortautomer thereof, wherein X is a single bond, —O(CH₂)_(p)— or—NR⁹(CH₂)_(p)—; R⁹ is hydrogen or (C₁-C₆)alkyl; and p is 1, 2, 3, 4, 5or
 6. 8. The compound of claim 7, wherein R² is halogen.
 9. The compoundof claim 7, wherein R^(4a) and R^(4b) are each independently hydrogen.10. The compound of claims 7, wherein R⁶ is aryl or heteroaryl, whereinsaid aryl and heteroaryl are optionally substituted at a substitutableposition with one or more substituents selected from the groupconsisting of (a) halogen; (b) cyano; (c) nitro; (d) hydroxy; (e)—NR¹⁴R¹⁵; (f) —C(O)R⁹; (g) —C(O)NR^(8a)R^(8b); (h) —NR⁷C(O)R⁹; (i)—OC(O)NR^(8a)R^(8b); (j) —NR⁷C(O)OR⁹; (k) —C(O)OR⁹; (l) guanidino; (m)heterocyclyl; (n) phenyl; (o) phenyloxy; (p) benzyl; (q) benzyloxy; (r)sulfamoyl; (s) (C₁-C₆)alkylsulfonyl; (t) (C₁-C₆)alkylaminosulfonyl; (u)di(C₁-C₆)alkylaminosulfonyl; (v) (C₁-C₆)alkyl optionally substituted bymono-, di-, or tri-halogen; (w) (C₁-C₆)alkoxy optionally substituted bymono-, di-, or tri-halogen; and (x) (C₁-C₆)alkylthio optionallysubstituted by mono-, di-, or tri-halogen; R⁷ is hydrogen or(C₁-C₆)alkyl; in each instance, independently, R^(8a) and R^(8b) areselected from (i) or (ii) as follows: (i) R^(8a) and R^(8b) are eachindependently selected from hydrogen or (C₁-C₆)alkyl; or (ii) eachR^(8a) and R^(8b), together with the N to which they are bonded,independently may form a 3 to 8 membered saturated or unsaturated ringoptionally containing one or more O or S atoms, or one or moreadditional N atoms, in the ring; in each instance, independently, R¹⁴and R¹⁵ are selected from (i) or (ii) as follows: (i) R¹⁴ and R¹⁵ areeach independently selected from (a) hydrogen; (b) (C₁-C₆)alkyl; (c)phenyl; (d) (C₁-C₆)alkyl substituted by aryl, hydroxy, carboxy oralkoxy; (e) (C₁-C₆)alkyl substituted by mono-, di-, or tri-halogen; or(f) (C₃-C₇)cycloalkyl; or (ii) each R¹⁴ and R¹⁵, together with the N towhich they are bonded, independently may form a 3 to 8 memberedsaturated or unsaturated ring optionally containing one or more O or Satoms, or one or more additional N atoms, in the ring.
 11. The compoundof claim 7, having formula III:

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer ortautomer thereof, wherein R⁹ is hydrogen.
 12. The compound of claims 11,wherein R⁶ is aryl or heteroaryl, wherein said aryl and heteroaryl areoptionally substituted at a substitutable position with one or moresubstituents selected from the group consisting of (a) halogen; (b)cyano; (c) nitro; (d) hydroxy; (e) —NR¹⁴R¹⁵; (f) —C(O)R⁹; (g)—C(O)NR^(8a)R^(8b); (h) —NR⁷C(O)R⁹; (i) —OC(O)NR^(8a)R^(8b); (j)—NR⁷C(O)OR⁹; (k) —C(O)OR⁹; (l) guanidino; (m) heterocyclyl; (n) phenyl;(o) phenyloxy; (p) benzyl; (q) benzyloxy; (r) sulfamoyl; (s)(C₁-C₆)alkylsulfonyl; (t) (C₁-C₆)alkylaminosulfonyl; (u)di(C₁-C₆)alkylaminosulfonyl; (v) (C₁-C₆)alkyl optionally substituted bymono-, di-, or tri-halogen; (w) (C₁-C₆)alkoxy optionally substituted bymono-, di-, or tri-halogen; and (x) (C₁-C₆)alkylthio optionallysubstituted by mono-, di-, or tri-halogen; R⁷ is hydrogen or(C₁-C₆)alkyl; in each instance, independently, R^(8a) and R^(8b) areselected from (i) or (ii) as follows: (i) R^(8a) and R^(8b) are eachindependently selected from hydrogen or (C₁-C₆)alkyl; or (ii) eachR^(8a) and R^(8b), together with the N to which they are bonded,independently may form a 3 to 8 membered saturated or unsaturated ringoptionally containing one or more O or S atoms, or one or moreadditional N atoms, in the ring; in each instance, independently, R¹⁴and R¹⁵ are selected from (i) or (ii) as follows: (i) R¹⁴ and R¹⁵ areeach independently selected from (a) hydrogen; (b) (C₁-C₆)alkyl; (c)phenyl; (d) (C₁-C₆)alkyl substituted by aryl, hydroxy, carboxy oralkoxy; (e) (C₁-C₆)alkyl substituted by mono-, di-, or tri-halogen; or(f) (C₃-C₇)cycloalkyl; or (ii) each R¹⁴ and R¹⁵, together with the N towhich they are bonded, independently may form a 3 to 8 memberedsaturated or unsaturated ring optionally containing one or more O or Satoms, or one or more additional N atoms, in the ring.
 13. The compoundof claim 7 wherein R² and R³ are each —N(CH₃)₂.
 14. The compound ofclaim 7, having formula IV:

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer ortautomer thereof, wherein R² is halogen; each R¹⁶ is independently (a)hydrogen (b) halogen; (c) cyano; (d) nitro; (e) hydroxy; (f) —NR¹⁴R¹⁵;(g) —C(O)R⁹; (h) —C(O)NR^(8a)R^(8b); (i) —NR⁷C(O)R⁹; (j)—OC(O)NR^(8a)R^(8b); (k) —NR⁷C(O)OR⁹; (l) —C(O)OR⁹; (m) guanidine; (n)heterocyclyl; (o) phenyl; (p) phenyloxy; (q) benzyl; (r) benzyloxy; (s)sulfamoyl; (t) (C₁-C₆)alkylsulfonyl; (u) (C₁-C₆)alkylaminosulfonyl; (v)di(C₁-C₆)alkylaminosulfonyl; (w) (C₁-C₆)alkyl optionally substituted bymono-, di-, or tri-halogen; (x) (C₁-C₆)alkoxy optionally substituted bymono-, di-, or tri-halogen; and (y) (C₁-C₆)alkylthio optionallysubstituted by mono-, di-, or tri-halogen; and q is 0, 1, 2, 3, 4 or 5.15. The compound of claim 14, wherein each R¹⁶ is independently (a)hydrogen (b) halogen; (c) cyano; (d) nitro; (e) hydroxy; (f) —NH₂; (g)—NH(C₁-C₆)alkyl; (h) —N((C₁-C₆)alkyl)₂; (i) —NHC(O)(C₁-C₆)alkyl; (j)—C(O)(C₁-C₆)alkyl; (k) —CO₂H; (l) —C(O)O(C₁-C₆)alkyl; (m) phenyl; (n)phenyloxy; (o) benzyl; (p) benzyloxy; (q) sulfamoyl; (r)(C₁-C₆)alkylsulfonyl; (s) (C₁-C₆)alkylaminosulfonyl; (t)di(C₁-C₆)alkylaminosulfonyl; (u) (C₁-C₆)alkyl optionally substituted bymono-, di-, or tri-halogen; (v) (C₁-C₆)alkoxy optionally substituted bymono-, di-, or tri-halogen; or (w) (C₁-C₆)alkylthio optionallysubstituted by mono-, di-, or tri-halogen.
 16. The compound of claim 7,having formula V:

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer ortautomer thereof.
 17. The compound of claim 16 wherein R² is halogen.18. The compound of claim 16 wherein R² is halogen; and R³ is —N(CH₃)₂.19. The compound of claim 1, having the formula

or a pharmaceutically acceptable salt, solvate, hydrate or tautomerthereof.
 20. The compound of claim 1, having the formula

or a pharmaceutically acceptable salt, solvate, hydrate or tautomerthereof.
 21. The compound of claim 1, having the formula

or a pharmaceutically acceptable salt, solvate, hydrate or tautomerthereof.
 22. The compound of claim 1, having the formula

or a pharmaceutically acceptable salt, solvate, hydrate or tautomerthereof.
 23. The compound of claim 1, having the formula

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer ortautomer thereof.
 24. The compound of claim 1, having the formula

or a pharmaceutically acceptable salt, solvate, hydrate or tautomerthereof.
 25. The compound of claim 1, having the formula

or a pharmaceutically acceptable salt, solvate, hydrate or tautomerthereof.
 26. The compound of claim 1, having the formula

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer ortautomer thereof.
 27. The compound of claim 1, having the formula

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer ortautomer thereof.
 28. The compound of claim 1, having the formula

or a pharmaceutically acceptable salt, solvate, hydrate or tautomerthereof.
 29. The compound of claim 1, having the formula

or a pharmaceutically acceptable salt, solvate, hydrate or tautomerthereof.
 30. The compound of any of claims 1-6, having formula VI

or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer ortautomer thereof, wherein Y is NH, O or S; and R^(6a) is (a) hydrogen;(b) (C₁-C₆)alkyl; (c) (C₂-C₆)alkenyl; (d) (C₂-C₆)alkynyl; (e)(C₃-C₇)cycloalkyl; (f) (C₁-C₆)alkyl substituted by aryl or heteroaryl;(g) (C₂-C₄)alkenyl substituted by aryl or heteroaryl; (h) (C₁-C₆)alkylsubstituted by mono-, di-, or tri-halogen; (i) (C₁-C₆)alkoxy substitutedby mono-, di-, or tri-halogen; (j) (C₁-C₆)alkylthio substituted bymono-, di-, or tri-halogen; (k) aryl; or (l) heteroaryl, wherein saidaryl and heteroaryl are optionally substituted at a substitutableposition with one or more substituents selected from the groupconsisting of (a) halogen; (b) cyano; (c) nitro; (d) hydroxy; (e)guanidino; (f) heterocyclyl; (g) phenyl; (h) phenyloxy; (i) benzyl; (j)benzyloxy; (k) —NR¹⁴R¹⁵; (l) —C(O)R⁹; (m) —C(O)NR^(8a)R^(8b); (n)—OC(O)NR^(8a)R^(8b); (m) —NR⁷C(O)R⁹; (n) —C(O)OR⁹; (o) —NR⁷C(O)OR⁹; (p)sulfamoyl; (q) (C₁-C₆)alkylsulfonyl; (r) (C₁-C₆)alkylaminosulfonyl; (s)di(C₁-C₆)alkylaminosulfonyl; (t) (C₁-C₆)alkyl optionally substituted bymono-, di-, or tri-halogen; (u) (C₁-C₆)alkoxy optionally substituted bymono-, di-, or tri-halogen; and (v) (C₁-C₆)alkylthio optionallysubstituted by mono-, di-, or tri-halogen.
 31. A pharmaceuticalcomposition comprising a compound of claim 1 and one or morepharmaceutically acceptable carriers or excipients.
 33. A method fortreating an allergic disease, or a symptom thereof, comprisingadministering a compound of claim
 1. 34. A method for treating aneosinophil-related disease, or a symptom thereof, comprisingadministering a compound of any of claim
 1. 35. A method for treating abasophil-related disease, or a symptom thereof, comprising administeringa compound of any of claim
 1. 36. A method for treating an inflammatorydisease, or one or more symptoms thereof, comprising administering acompound of any of claim
 1. 37. A method for treating a disease orcondition, or symptom thereof, wherein the disease or condition isselected from the group consisting of asthma, exercise induced asthma,allergic rhinitis, atopic dermatitis, allergic conjunctivitis,Churg-Strauss syndrome, sinusitis, basophilic leukemia, chronicurticaria, basophilic leukocytosis, psoriasis, eczema, inflammatorybowel disease, ulcerative colitis, Crohn's disease, COPD (chronicobstructive pulmonary disorder) and arthritis, the method comprisingadministering a compound of any of any claim
 1. 38. The method of claim37, wherein the disease or condition is selected from the groupconsisting of asthma, exercise induced asthma, allergic rhinitis, atopicdermatitis and allergic conjunctivitis.
 39. The method of claim 37,wherein the disease or condition is selected from the group consistingof Churg-Strauss syndrome and sinusitis.
 40. The method of claim 37,wherein the disease or condition is selected from the group consistingof basophilic leukemia, chronic urticaria and basophilic leukocytosis.41. The method of claim 37, wherein the disease or condition is selectedfrom the group consisting of psoriasis, eczema, inflammatory boweldisease, ulcerative colitis, Crohn's disease, COPD (chronic obstructivepulmonary disorder) and arthritis.
 42. The method of claim 33, whereinthe compound is administered orally, parenterally or topically.
 43. Themethod of claim 33, wherein the compound is administered in combinationwith a second therapeutic agent.
 44. The method of claim 43, wherein thesecond therapeutic agent is useful for treating asthma, exercise inducedasthma, allergic rhinitis, atopic dermatitis, allergic conjunctivitis,Churg-Strauss syndrome, sinusitis, basophilic leukemia, chronicurticaria, basophilic leukocytosis, psoriasis, eczema, inflammatorybowel disease, ulcerative colitis, Crohn's disease, COPD (chronicobstructive pulmonary disorder), arthritis, or a symptom thereof.